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Tuberculosis and Clinically used Antitubercular Drugs: Particularly for Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis

Author(s): Mohammad Asif
Abstract:
Tuberculosis and Clinically used Antitubercular Drugs: Particularly for Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis
Authors
Mohammad Asif
Department of Pharmacy, Himalayan Institute of Pharmacy and Research, Dehradun, Uttarakhand, India
Publication Month and Year: January 2020
Pages: 78
E-BOOK ISBN: 978-81-944644-9-5
Academic Publications
C-11, 169, Sector-3, Rohini, Delhi, India
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Tuberculosis and Clinically used Antitubercular Drugs: Particularly for Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis
Infectious diseases originated by microorganisms and have increased severely in current years. In spite of numerous important advances in antimicrobial chemotherapy, the extensive use and misuse of these antimicrobial and antibiotic drugs have caused the emergence of microbial resistance to antimicrobials and antibiotics, which is a serious risk to public health. In particular, the emergence of multidrug resistant (MDR) bacteria has become a serious difficulty in the chemotherapy of bacterial diseases. Therefore, the progress of new compounds to deal with resistant microorganism has become one of the most essential areas of antimicrobial research today. In addition to the development of new and efficient antibacterial agents against MDR-gram positive bacteria, recently concentration has focused on the treatment of tuberculosis (TB). Therefore, recent developments have been directed toward investigating currently used and newly developed anti-TB drugs and their toxicities and mechanisms.
Keywords: ant tuberculosis, drug resistant, mycobacterium, chemotherapy
Introduction
TB is one of the oldest and most invasive, respiratory spread diseases in history. According WHO report, TB has spread to every area of the world. As much as one-third of the world's population is presently infected, more than any other infectious microbial disease and the predictable 8.8 million new cases every year communicate to 52,000 deaths per week or more than 7,000 each day (Okada and Kobayashi 2000; Mayekar et al., 2010). These numbers however, are only a partial representation of the world TB threat. It was predictable that nearly 1 billion more people will be infected with TB in the coming 20 years. However, the overall number of new TB cases is still growing slowly, 95% occur in developing nation every year and about one million young women per year are offended with this infectious disease in the developing world (WHO, 2007). The occurrence of TB is linked to dense population, poor sanitation and, poor nutrition (Dony et al., 2004; Surendra et al., 2010). Observed Treatment, short-course (DOTS) approach, comprises the basis of the present protocol for control of TB. However, the three main drugs, isoniazide (INH), pyrazinamide (PZA) and rifampicin (RIF) used in the treatment are potentially hepatotoxic and may directed to drug associated hepatitis. Despite the undisputed achievement of DOTS strategy, the emergence of MDR-TB strains, persistently isolated from patient's sputum, darken the future (Omar and Ahmed 2008). The enhancement in TB prevalence during recent years is mainly due to the occurrence of TB is synergy with Human Immunodeficiency Virus (HIV) pandemic, which enhance the risk of rising the disease 100-fold where 31% of new TB cases were attributable to HIV co-infection, and as well as the emergence of MDR-TB strains (Elsayed et al., 2000).
The management of MDR-TB has become a key concern worldwide. In addition to this, the enhancement in Mtb strains resistant to front line anti-TB drugs like RIF and INH has additional complications, which noticeably point out the requirement for more effective anti-TB drugs for the efficient treatment of TB (Management of MDR-TB 2009). The main drugs (first line) used in the regimen are exhibited serious adverse effects such as severe damage to the eighth cranial nerve, hypersensitivity reactions, irreversible impairment of auditory functions (streptomycin or SM), potentially hepatotoxic and may direcedt to drug related hepatitis (INH, PZA and RIF and thrombocytopenic purpura (RIF). Second line anti-TB drugs are more toxic than first line anti-TB drugs, amikacin and kanamycin affects kidney damage and hearing loss, viomycin and capreomycin causes eighth cranial nerve toxicity and nephrotoxicities. The Fluoroquinolones (FQs) (ciprofloxacin (CPX), moxifloxacin (MXF), ofloxacin (OFX) (levofloxacin (LVX), the chiral form of OFX is more potent), trovafloxacin, enofloxacin and sparfloxacin etc). The FQs are ever more contraindicated for patients due to growing occurrence of drug resistance. Ethionamid and prothionamide (analogues of INH) causes adverse effects such as GIT disorders (like anorexia, salivation, abdominal pain, nausea, and diarrhea), diverse mental turbulence (such as depression, psychosis, anxiety, dizziness, drowsiness and headache) and hypersensitivity. Cycloserine causes adverse effects are mainly CNS manifestations like irritability, headache, depression, convulsions. The p-amino salicyclic acid (PASA) causes g.i.t. problems sch as nausea, anorexia, abdominal distress, epigastric pain, diarrhea, peptic ulcers and hypersensitivities (Kamal et al., 2008; Da Silva et al., 2003; Rieder et al., 2001).
The TB is a chronic communicable disease caused by the mycobacterium strains, including mainly Mtb, that divides every 16 to 20 hrs, an very slow rate compared with other bacterias, which are generally divide in less than an hour, but also M. africanum, M. bovis, M. canetti, and M. microti can also cause TB, but these species do not generally infect healthy adults. The TB is an airborne infectious disease caused by communication of aerosolized droplets of Mtb. The principal source of infection is viable tubercular bacilli, expelled in the environment by a patient with active TB. Mycobacterium is a genus of bacteria, which grows slowly under aerobic circumstances and is distinguished by acid-fast staining method. The Mycobacterium is non-motile, Gram positive, rod-shaped, obligate aerobic bacteria that belong to the order actinomycetales and family Mycobacteriaceae. Several species, including Mtb, M. bovis, M. microti, M. canetti, M. kansasii, M. africanum, M. avium and M. leprae are the intracellular pathogens of higher vertebrates. The Mtb complex comprises three other TB-causing mycobacteria: M. africanum, M. bovis and M. microti. The first two only extremely seldom cause disease in immuno capable people. On the other hand while M. microti is not generally pathogenic, it is possible that the pervasiveness of M. microti infections has been under expected. Other pathogenic mycobacteria are M. leprae, M. avium and M. kansasii. The non tuberculous mycobacterium (NTM) causes neither TB nor leprosy, but they do cause pulmonary infections resembling TB. The TB requires much longer time of cure to entirely remove mycobacteria from the body. The cell wall of Mycobacterium species in its full structural and efficient integrity is crucial for its growth and survival in the contaminated host (Shafii et al., 2008; Nagarajan et al., 2008).
Immunology
M. tuberculosis is the causative organism of TB. It is transmitted through the air as suspended droplets and inhaled by persons into lungs. The organism reaches the deepest of alveoli in their lungs, where the organism avoids destruction by alveolar macrophages and maintains itself in the intracellular atmosphere (Ottenhoff and Kaufmann. 2012; Charles, et al., 2013; Kaufmann. 2010). Once Mtb causes initial infection in the lungs; innate immunity will be activated. Dendritic cells and alveolar macrophages are transported to the infected site to control the pathogen. Active TB occurs when the organism is released from the granuloma. This is because dendritic cells and the macrophages fail to control the pathogen and causes necrosis of granuloma (Schwander and Dheda. 2011). In many cases of TB, humans are infected by the organism but they do not grow the disease. These cases are classified as latent TB infection (LTBI) where the people are the vast reservoir for the organism. Such LTBI will reactivate when the immune system of the person weakens, most notable in individuals with HIV infection (Beresdord and Sadoff. 2011). LTBI occurs when immune system restrains the spread of Mtb by the formation of granuloma. However, it does not kill all the pathogen where the organism survives inside the granuloma. In some studies, it is believed that the CD4+ Th1-cells are also involved in controlling TB infection. However, due to some unknown reasons, the T-cell response is muted within the granuloma with limited antigen appearance and recognition (Charles, et al., 2013). Th17 that is produced by IL-17 received attention lately due to some evidence suggesting that Th17 cells are involved in controlling TB infection. Besides that, apoptosis of the cells is caused by CD 8+ T-cells also plays an important role in TB infections (Ottenhoff and Kaufmann. 2012). Though the mechanisms of the immune system controlling the TB bacilli are not well understood, scientists believe it is the cell-mediated immunity that plays an important and critical role (Svenson, et al., 2010).
Pathophysiology of TB
TB is is a hypersensitive granulomatous infectious disease caused by Mtb. In India 40% people are affected by T.B. So need of information about T.B. and pathophysiology of T.B. to people. Pathophysiology means, when a human or animal suffering from a disease this is because deranged or change in function on that organ or human body. Infection is caused by air- borne droplets of organisms person to person. The main object is how to diagnose and how it is cure or treat. It is diagnosed by PPD, IGRA, Sputum studies, X-rays and Biopsies. Mostly antibiotics are preferred for the first treatment.
Etiology of tuberculosis (Alexander et al., 2015)
M. tuberculosis-most common cause
Other than tuberculosis-includes
a.M. aviumintracellularee.M. ulcerence
b.M. kansasif.M. fortuitum
c.M. scrofulaceumg.M. chelonei
d.M. marinum
Sites involved for TB infection (Hachart et al., 2016)
Sites involved
a.Pulmonary tb-85% of all TB casese.Bones & joints
b.Extrapulmonary sitesf.Meninges
c.Lymph nodeg.Intestine
d.Genito-urinary tracth.Skin
Characteristics of M. tb (Alexander et al., 2015)
Characteristics
a.Rod shape, 0.2-0.5 in D, 2-4 in Ld.Aerobic and non motile
b.My colic acid present in its cell wall, makes it acid faste.Can remain dormant for decades
c.So it resists decolourization with acid & alcoholf.Multiplies slowly
How is TB Transmitted (Hachart et al., 2016)
TB Transmittion
A.Person-to-person through the air by a person with active TB disease of the lungs.
B.Less frequently transmitted by1.Ingestion of M. bovis found in unpasteurized milk products or autoingestion.
2.Inoculation (in skin TB)
3.Transplacental route (rare route)
Pathogenesis and morphology of TB (Alexander et al., 2015)
S. No.PathogenesisS. No.Morphology (Primary TB)
1.M.tuberculosis starts a IV hypersensitivity immune reaction inside the lung which damages the lung tissue while killing the foreign microbes.1.Form of disease that develops in a previously unexposed person.
2.Almost always begins in lungs.
2.Pathologic manifestation of TB like caseating granuloma and cavitation are result of hypersensitivity that develops in concert with the protective host immune response.3.Inhaled bacilli implant in the distal airspaces of lower part of upper lobe or upper part of lower lobe.
4.It forms a small sub pleural parenchymal lesion in the mid zone of the lung (ghon focus inflammation +caseous necrosis)
3.Macrophages are the primary cells infected by M.tuberculosis.5.Tubercle bacilli drain to the regional lymph node which also often undergoes caseous necrosis.
6.Parenchymal lung lesion+Nodal involvement= Ghon’s complex.
Histologically: Granulomatous inflammation forms both caseating and non caseating tubercles. Tuberculous Granuloma has the following characteristics:
S. No.HistologyS. No.Histology
1.Central caseous necrosis3.Langhans giant cells
2.Transformed macrophages called epithelioid cells4.Lymphocytes, plasma cells, and fibroblasts
Pathophysiology of TB (Hunter et al., 2014)
The Three Distinct Stages Hypothesized (Hachart et al., 2016)
Act I-The war of attritionAct II-The sneak attackAct III-The fallout
1.Mtb try to multiply while the host attempts to contain them within granulomas1.Act II Post-primary bronchogenic TB begins asymptomatically in the apices of the lung, at some distance from the site initial infection1.It is either coughed out to form a cavity or becomes surrounded by epithelioid cells and fibrosis.
2.With no or little immunity, there is greater lymphatic or hematogenous spread2.It is part of latent TB since there are no clinical symptoms2.This produces granulomatous inflammation and most clinical disease
3.Control is through cell mediated Immunity3.Few numbers of Mtb in modified alveolar macrophages drive accumulation of host lipids and mycobacterial antigens in an isolated section of lung in form for a sudden necrotizing reaction adequate to produce a cavity further progress of necrotic caseous pneumonia3.Cavities form when caseous stage encompasses the pneumonia softens, fragments and is coughed out of the body leaving a hole
4.Pneumonia that is not coughed out remains to induce inflammation. It dries to become fibrocaseous TB
Symptoms of tuberculosis (Hachart et al., 2016; Hunter et al., 2014)
If a patient has any of the following, consider him a 'Tuberculosis Suspect':
S. No.Symptoms of TB
1.Cough for over 3 weeks
2.Haemoptysis
3.Pain in the chest for over 3 weeks
4.All these can be due to some other diseases but sputum must be tested if any of the symptoms are present
Cough and sputum is very common everywhere. Much of this is due to acute respiratory infections and lasts only a week or two. There is also much chronic cough due to chronic bronchitis (sometimes called 'Chronic Obstructive Pulmonary Disease' (COPD or other names). This is mostly due to tobacco smoking, but may also occur from atmospheric pollution (either due to cooking or heating fires or in some places due to industrial pollution). (Hachart et al., 2016).
S. No.General symptomsS. No.Respiratory symptoms
1.Loss of weight1.Cough5.Amenorrhea
2.Fever and sweating2.Sputum6.Arrhythmia
3.Loss of appetite3.Blood-spitting7.Hoarseness
4.Breathlessness4.Tiredness
Diagnosis (Hunter et al., 2014)
S. No.Clinical CluesS. No.Clinical Clues
1.Cough > 2 weeks4.Chronic immune suppression
2.Fever > 2weeks5.Endemic country
3.Exposure to TB6.Abnormal physical exam
Laboratory tests (Hunter et al., 2014)
TB test is the mantoux skin test (PPD)
•A small amount of fluid (called tuberculin) is injected into the forearm just under the skin
•A health professional should read the test 48 to 72 hours after it is administered to check for a reaction
•If there is a reaction (swelling), more testing is done. The Tine test (which uses a 4-pronged device) is no longer recommended because it is not as effective in delivering the proper amount of tuberculin under the skin. (Harries et al., 2016)
Mycobacterial Examination-Mycobacterial examination has 6 stages
S. No.Mycobacterial examinationS. No.Mycobacterial examination
1.Proper specimen collection4.Drug susceptibility testing
2.Examination of acid‐fast bacilli (AFB) smears5.Specimen culturing and final identification
3.Direct identification (NAAT‐nucleic acid amplification test)6.TB genotyping
Specimen Sources (Harries et al., 2016)
S. No.SpecimenS. No.Specimen
1.Sputum (primary)5.Blood
2.Pulmonary aspiration (secondary)6.Urine
3.Body fluids (CSF, pleural, peritoneal, etc)7.Gastric aspirate
4.Tissue biopsy8.Stool (special request)
Acidfast Bacilli (AFB) smear (Harries et al., 2016)
S. No.Acid‐fast Bacilli (AFB) smear
1.Least sensitive of all AFB Tests (20‐75% positivity)
2.Requires 10,000 AFB/ml to be positive
3.Positive slide does not differentiate TB from atypical mycobacteria (i.e. M. avium)
4.Reported within 24 hours of receiving the sp ecimen in the laboratory.
Fluorescent AFB smear using auramine-O staining
S. No.Fluorescent AFB smear using auramine‐O staining
1.Very sensitive, takes minutes to read
2.Not all that is fluorescent is AFB (need a care ful eye)
3.Chemical fluorescence, notan immune stain or Direct Fluorescent Antibody
4.Can be confirmed with Ziehl Neelson (ZN) smear
5.NAA (Nuclic acid amplification) testing should be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities.
6.NAAT should be performed on all new AFB+ sputum specimens
MTD-hologicand gene xpert-cepheid are the only FDA approved methods
NAA tests are available that are not FDA approved, such as real time PCR assays. MDHHS performs a real time lab developed PCR test to detect Mtband MAC using the ABI 7500 Fast DX.
AFB culture test
S. No.AFB culture test
1.More sensitive than AFB smear
2.10 AFB/ml can produce a positive result, whereas AFB smear needs 10,000 AFB/ml
3.Culture may be AFB positive even if smear was negative for AFB
Tests performed on growth in mycobacteria culture
S. No.Tests performed on growth in mycobacteria culture
1.Accuprobe DNA test (not amplified)
2.HPLC (high performance liquid chromatography)
3.MALDI‐TOF (matrix assisted laser desorption ionization time of flight)
4.Biochemical Identification Confirmation
5.Drug Susceptibility
Susceptibitility testing of Mtb
S. No.
1.Repeat after 90 days of therapy, if specimens continue to produce Mtb
2.Relapse or failed therapy
Additional Molecular Tests for TB
CDC (center for disease control)-molecular detection of TB drug resistance (MDDR) and CDC MDDR (Harries et al., 2016)
S. No.CDC-MDDRS. No.CDC-MDDR
1.Rapid testing for DNA mutations associated with drug resistance1.First‐line MDDR to detect MDR‐TB
2.NAAT (+) sputum specimens or culture isolates (prior approval)2.rpoB (Rifampin)
3.Must meet the following criteria3.inhA and katG(Isoniazid)
4.Known Rifampin resistance4.Second‐lineMDDR to detect XDR‐TB
5.Known MDR5.gyrA mutation (Fluoroquinolones)
6.High risk of Rifampin resistance or MDR‐TB6.eis mutation (Kanamycin)
7.High profile patient (e.g. daycare worker, nurse)7.tlyA gene (Capreomycin)
8.Mixed or non‐viable culture8.pncA muttion (Pyrazinamide)
9.Drug Adverse reaction (e.g. Rifampin allergy)9.embB mutation (embB306) (Ethambutol)
TB DNA Genotyping (Hachart et al., 2016)
S. No.TB DNA genotyping
1.Universally Offered by CDC
2.DNA “Fingerprint” of each isolates
3.Michigan Department of Health & Human Services laboratory runs genotype on all TB cultures in USA and territories
Treatment: The standard four drugs (yes, all at once) for starting treatment for TB in the US are:
•Isoniazid (INH) •Rifampin •Pyrazinamide (PZA) •Ethambutol. Ok, so you take your pills-for 6-8 months (Hachart et al., 2016).
Antibiotics used to treat “TB” of all kinds: •Rifampicin. •Rifabutin. •Ciprofloxacin. •Amikacin. •Ethambutol. •Streptomycin. •Clarithromycin. •Azithromycin.
DrugAdverse reactionsComments
IzoniazidHepatitis, drug interactions, numbness, tingling, pain in extremities, fatigueRaises Dilantin and INH blood serum levels if taken together; this may lead to toxicity
RifampinStomach upset, Symptoms of Flu, Bleeding, Rashes, HepatitisIf you are taking other drugs (such as birth control pills) consult your doctor. Rifampin can turn body fluids orange but this is temporary.
PyrazinamideJoint aches, Hepatitis, Rashes, Stomach upset, Gout (rarely)Avoid in pregnancy
EthambutolVisual ProblemsShould not be used in young children whose vision can't be tested unless there is drug resistant TB
Unique problems associated with mycobacteria
The Mtb is extremely complex external cellular membrane. These are intracellular bacteria and capability to colonize macrophages–in the lung, the Mtb cell (tubercle bacilli) is engulfed by macrophages, which surrounded the bacteria into the phagosome section. Characteristically, the phagosome fused with the lysozome which have degradative enzymes, low pH and reactive oxygen species etc., to devastated foreign elements. The fusion regularly does not occur with Mtb and the bacterium continues to exist in the cell planned to kill it. As the bacterium developing, it kills the macrophage, producing more bacteria to be taken up by extra macrophages. Other macrophages and T-cells are employed to the site and assemble around the infected cells after ~2-3 weeks. Structural components in the Cell covering of Mtb are presentation interaction of Methyl-branched long-chain components with a mycolic acid surrounding substance. Mycolyl arabinogalactan (mAG) is linked by a phosphoryl linker unit to peptidoglycan (PG). Complex free lipids act together with mAG. Lipoarabinomannan (LAM) and phosphatidyl inositol pentamannoside (PIM5) are exhibited attached in the plasma membrane (fig 1.20).
Fig 1: Structure of mycobactrium cell membrane
Tuberculosis-HIV combination
The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB (WHO. 2002). As per WHO statement, about 90% of the patients containing both TB and HIV died within a only some months after clinical indications were arisen. Thus, WHO warned the world for ‘‘even bigger TB-HIV crisis’’ and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. As per WHO, HIV is spreading quickly in India with the biggest number of TB cases in all around the world (Espinal 2003; Amalio and Michael 2000).
Drug-resistant tuberculosis
Drug resistance presented by Mtb is an important problem for the treatment, prevention and control of TB. This resistance has conventionally been recognized to the unusual multi-layer cell envelope and active multidrug efflux pumps. Recent approaches to the mechanisms that neutralize the toxicities of antibiotic drugs in the cytoplasm have exposed other systems that purpose in synergy with the permeability barrier and efflux systems to offers natural resistance. Drugs inhibiting these intrinsic systems would permit various antibiotics, which are already presente but have not been used for TB, to expand latest activities against Mtb (Global Tuberculosis Control 2008).
Multi drugs resistance-tuberculosis
The MDR-TB refers to instantaneous resistance to at least two or more first-line anti-TB drugs (INH, RIF, PZA, EMB, and SM) (Barry et al., 2000). The MDR take place from sharing of genes between various species or genera, normally mediated by minute pieces of extra-chromosomal DNA identified as plasmids or transposons. Treatment for MDR-TB is less effective, long lasting, costly and weakly tolerated (Kamal et al., 2008).
Extensively drug resistant tuberculosis
The XDR-TB is defined as the resistance to at least INH and RIF in adding together to any quinolones and at least one injectable second-line drug (any FQs, amikacin, capreomycin and kanamycin). The aim of treatment for MDR-TB and XDR-TB are the identical. The major difference is that XDR-TB is connected with a much higher mortality rate than MDR-TB, because of decreased number of valuable treatment alternatives. So there is a vital need for novel drug molecules that are effective against Mtb in order to reduce the time duration of TB therapy.
Chemotherapy of tuberculosis
First line anti-TB drugs
Treatment of TB are principally depends on first-line anti-TB drugs (fig. 1), which comprises SM, INH, RMP, EMB and PZA, these are more effective and less toxic effects as compare to second-line anti-TB drugs (Kamal et al., 2008).
IsoniazidPyrazinamideEthambutol
R = CH3 Rifampicin R = CHO Streptomycin
R = CH2CH (CH3)2 Rifabutin R = CH2OH dihydrostreptomycin
R = Rifapentine
Fig 2: Structures of first line anti-TB drugs
Table 1: Currently used antituberculosis drugs
Essential first-line antituberculosis drugs
Isoniazid
Rifampicin
EthambutolPyrazinamide
Streptomycin
Second-line parenteral agent (injectable antit-TB drugs)
Kanamycin
AmikacinCapreomycin
Fluoroquinolones
Ciprofloxacin
Ofloxacin
LevofloxacinMoxifloxacin
Gatifloxacin
Oral bacteriostatic second-line anti-TB drugs
Ethionamide
Prothionamide
CycloserineTerizidone
p-aminosalicylic acid
Other drugs anti-TB drugs
Clofazimine
Linezolid
Amoxycillin-clavulanateThioacetazone
Clarithromycin
Imipenem
Thioridazone
Second line anti-TB drugs
According to world health organization (WHO) there are six drugs of second line anti-TB drugs that are used in the chemotherapy of TB (Center for Disease Control 2006). A drug may be categorized as a second-line anti-TB drug because of one of two potential reasons:
1)It may be less active than the first-line anti-TB drugs or it may have more toxic side-effects
2)These involve of different classes of compounds namely, aminoglycosides (fig. 2): (amikacin, kanamycin), polypeptide analouges (fig. 2): (viomycin, capreomycin), FQs (fig. 3): (CPX, MXF, OFX etc), thioamides: (prothioamide, ethionamides), cycloserine and para-aminosalicylic acid (fig. 4)
Amikacin capreomycin
ViomycinKanamycinCylcoserine
Fig 3: Structures of different antibiotics (second line drugs)
CiprofloxacinMoxifloxacinSparfloxacin
R/S: GatifloxacinR/S: Ofloxaci EnofloxacinS: Levofloxacin
Fig 4: Structures of different fluoroquinolones (second line anti-TB drugs)
EthionamideThioridazinep-Aminosalicylic acidProthionamide
Fig 5: Structures of different second line drugs
Multidrug therapy: Treatment of TB is very different from the treatment of other diseases due to the unique characteristics of Mtb. There are some basic necessities for the successful treatment of TB. Firstly, the treatment must consist of a mixture of antibiotics to prevent the selection of a resistant strain. Secondly, the antibiotics must be given for a least period of 6 months to fully eliminate the bacteria so that there is no chance of relapse once treatment is completed. Finally, health care professionals must monitor the patient for observance to the drug schedule as well as any linked drug-induced toxicities. Two phase concept of TB treatment first is an early bactericidal or “intensive” phase which is followed by a following sterilizing or “continuation” phase. The most of infecting bacilli are killed during the bactericidal phase thereby reducing clinical symptoms, risk of spread and emergence of drug resistance (DR) (Sarkar et al., 2016). In the successive sterilization phase, the residual slower growing populations are eliminated, thereby reducing the chance of relapse. Amusingly, some of the first-line drugs like INH are highly effective for the first bactericidal phase but have poor sterilizing action, whereas PZA is a strong sterilizing drug with poor bactericidal action (Sarkar et al., 2016; Mitchison. 2000). During efficient treatment, the fast growing bacteria population is killed in the early time and patients show negative culture within 2 months of the treatment. The residual slow growth population accounts for deteriorations and is the reason for prolonged treatment. Most anti-TB drugs are bactericidal while it is dividing, which explains why more time is needed to kill the slow growth bacterial population.
Table 1: Preferred drug treatment
RankingInitial phaseContinuation phase
PreferredINH, RIF, PZA, EMB daily for 2 monthsINH, RIF daily for 4 months
INH, RIF, PZA, EMB, 3 times a week for 2 monthsINH, RIF, three times a week for 4 months
OptionalINH, RIF, PZA, EMB daily for 2 monthsINH, EMB daily for 6 months
Drugs for HIV/TB
Clarithromycin (fig. 5) is a macrolide antibiotic drug used in HIV infected TB patients to cure the M. avium complex (MAC). It has an analogous antimicrobial range as erythromycin, but is more efficient against certain Gram-negative bacteria, particularly Legionella pneumophila (Nagarajan et al., 2008). Thioacetazone (fig. 5) is valuable in stoping resistance to more influential drugs like INH and RIF. It is not at all used on its own to treat TB. The use of thioacetazone is declining because it can originates severe skin reactions in HIV positive patients. Thioridazine is also identified to kill MDR-TB. It is no longer suggested for treatment due its adverse effects like urination-difficulties, dry mouth, glaucoma and postural hypotension. The circumstances are further difficult by the emergence of MDR-TB and XDR-TB by infections with lethal synergy with HIV/AIDS. Patients with MDR-TB are being treated with a combination having second line drugs that are less active, more expensive and more toxic. TB is a lethal synergy with HIV/AIDS puts HIV positive patients with latent tubercle bacilli disease (LTBI) at a greater risk of developing active TB, making TB as the number one killer among patients with AIDS (Kamal et al., 2008).
ClarithromycinThioacetazone
Fig 6: Structures of drugs for HIV/TB
Properties and mechamism of currently used common anti-TB drugs
Primary agents
Isoniazid (Nydrazid, Laniazid)
It is bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. The INH is a close to ideal antibiotic and very selective (Mycobacteria-MIC value ~0.025-0.05μg/mL and other bacteria MIC vale >500μg/mL). The INH is an inexpensive with good oral availability and low toxicity. It Inhibits mycolic acid biosynthesis and target the enoyl-acyl carrier protein reductase enzyme (InhA) engaged in mycolic acid synthesis. The INH inactivation of IhhA needs metabolic activation. It is also utilized in combinations, INH and RIF and INH, RIF, and PZA.
Rifamycins
Rifamycins are the members of the ansamycin family and are natural products from Amicolaptosis mediterranei. These are active towards various bacteria but used almost exclusively against TB.
Rifampin (Rifadin)
Rifampin is a semisynthetic analogue of rifamycin and most effective anti-TB agent with MIC vale as low as 0.005μg/mL. it is used as oral or parenteral formulation, it can access CNS and it is sensitive to moisture
Rifapentine (Priftin)
Rifapentine is a cyclopentyl analogue of RIF. Benefit over rifampin is less repeated dosing. The RIF analogue inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks elongation of the RNA transcript and inhibits gene expression. It is also act as CYP450 inducer. One remarkable side effect is discoloration of body fluids. The RIFs are not suggested for use in HIV infected pateints. Two RIF analogues are existing for indications other than TB.
Rifabutin (Mycobutin): It is used mostly in MAC infections.
Rifaximin (Xifaxan): Indicated for treatment of traveler’s diarrhea
Ethambutol (Myambutol)
Ethambutol is a orally active (+) isomer and 16 time more potent than meso isomer and 200 time more potent than (-) isomer. Mycolic acids are bound covalently to peptidoglycan via arabinogalactan. The EMB inhibits the polymerization of cell wall arabinan, and results in the addition of the lipid carrier deca-prenol phosphoarabinose. The EMB may interfere with the transfer of arabinose to the cell wall acceptor. The EMB is generally bacteriostatic agent and effective only towards energetically dividing cells. It action is synergistic with RIF.
Pyrazinamide (Aldinamide)
Pyrazinamide is a pyrazine derivative of nicotinamide and its mechanism assumed to be analogous to INH based generally on structural resemblance, not direct confirmation. It has to be metabolically activated and PZA-resistant strains of Mtb contain a mutation in the hydrolase gene.
Streptomycin
Streptomycin is still considered a first line anti-TB drug but is used less frequently than the other drugs. It is bactericidal, inactive against intracellular bacilli and no action against M. avium. Resistance is frequently due to phosphorylation.
Secondary/retreatment agents
Aminosalicylic acid (P.A.S. parasal)
Para-aminosalicylic acid orally available as a range of salts and fell out of use because of adverse effects and frequent resistance. Related to sulfonamides, it is bacteriostatic and act as competitive inhibitor of enzyme mycobacterial dihydro pteroate synthase.
Ethionamide (Trecator SC)
Ethionamide is developed as a derivative of INH but less potent than INH. The mechanism of action is like as INH. The requires oxidative activation come into sight it is by an enzyme other than KatG projected to form a covalent connection with InhA.
Fig 7: Presently used anti-TB drugs and sites of action
1.2.8.2.3 Cycloserine (Seromycin)
Cycloserine is natural compound and restricted to being a retreatment because of CNS toxicity. It inhibits peptidoglycan formation, particularly-blocks the alteration of L-Ala to D-Ala.
L-Ala D-Ala
Fig 8: No cross-resistance with other anti-TB drugs
Capreomycin (Capastat)
Capreomycin is a constituent of the tuberactinomycin family of highly basic cyclic pentapeptides-generally with a sixth amino acid as a side chain. It is most active tuberactinomycins and blocks protein synthesis and interferes with initiation, tRNA selection and chain elongation. It binds to a site on 16S rRNA that is known by aminoglycosides and to the 23S rRNA. Some mycobacterium strains resistant to capreomycin are also resistant to kanamycin. Acetylation or phosphorylation and target alteration-rRNA methyltransferase.
Kanamycin
Most commonly used second-line aminoglycoside and only given by intra muscular (IM) administration.
Table 1: HO groups of first-and second-line anti-TB drugs
GroupDaily dose and comments
Group 1: First-line oral antituberculosis drugs
Isoniazid5 mg/kg only high-dose INH should be given in M/XDR-TB
Rifampicin10 mg/kg not indicated
Rifabutin5 mg/kg may have activity but indication is not clear
Ethambutol15-25 mg/kg
Pyrazinamide30 mg/kg
Group 2: Fluoroquinolones
Ofloxacin15 mg/kg less active than agents below
Levofloxacin15 mg/kg
Moxifloxacin7.5-10 mg/kg
Group 3: Injectable anti-TB drugs
Streptomycin15 mg/kg not recommended for MDR-TB
Kanamycin15 mg/kg
Amikacin15 mg/kg
Capreomycin15 mg/kg
Group 4: less-effective second-line anti-TB drugs
Ethionamide/prothionamide15 mg/kg
Cycloserine/Terizidone15 mg/kg
P-aminosalicylic acid150 mg/kg
Group 5: Less-effective drugs or drugs on which clinical data are light
Linezolid600 mg
Clofazimine110 mg
Amoxicillin with clavulanate875/125 mg every 12h
Imipenem500-1000 mg every 6 h
Clarithromycin500 mg/12 hour
High-dose isoniazid10-15 mg/kg good activity in setting of low-level resistance
Thioacetazone 150 mg150 mg
New anti-TB agents
The five first-line anti-TB drugs for therapy are highly active and the rate of severe adverse effects are low and six drugs of second line anti-TB drugs, that may be less effective as compare to the first-line anti-TB drugs or it may contain more toxic side-effects. Though, unpleasant side effects, comparatively long duration of therpy and non-compliance to regimen are drawbacks. The second line drugs used for MDR-TB are extra expensive, less efficient and more toxic than the first anti-TB drug regimen (Shafii et al., 2008; Nagarajan et al., 2008). The objective now is to develop new anti-TB drugs in a cost-effective way, which efficaciously treats transmittable MDR-TB/XDR-TB strains and latent infections with reduced treatment periods as well as less frequency of dosage. Some of newly discovered Anti-TB agents are discussed below.
Compounds originating from existing families of drugs
Using existing fluoroquinolones for TB?
Fluoroquinolones (FQs) were established into clinical apply in the 1980s. Differentiated by broad range antimicrobial agents and extensively used for the treatment of various bacterial infections (Bartlett et al., 2000; Neu, 1987). The FQs have been also originated to have anti-TB activity (Grosset, 1992; Tsukamura et al., 1985) and are presently used as part of the suggested regimen as second-line anti-TB drugs. Since FQs share the similar molecular targets and highly probable that they will activate the same mechanisms of resistance. In fact, cross-resistance has been accounted within the FQs class such that reduced vulnerability to one FQ possibly presented reduced vulnerability to all FQ derivatives (Alangaden et al., 1995; Ginsburg et al., 2003a; Ruiz-Serrano et al., 2000). The extensive use of FQs in other bacterial infections may choose for resistant strains of Mtb. The FQs vulnerability is not assessed in clinical Mtb isolates. The extensive use of FQSs for therapy of common microbial infection, resistance to FQs remains uncommon and occurs mostly in MDR strains. The cross-resistance was observed among the various FQ compounds tested (OFX, LVX, GAT, MXF, and CPX) (Ginsburg et al., 2003b). The rapid progresses of resistance are mostly when FQs are administered as the only active drugs in a failing multi-drug therapy (Alangaden and Lerner, 1997; Rodriguez et al., 2001; Sulochana et al., 2005; Yew et al., 1990). These new agents are presently taken in consideration as anti-TB drugs.
Gatifloxacin
Gatifloxacin (GAT) has found bactericidal activity against Mtb (Alvirez-Freites et al., 2002). The GAT revealed the highest bactericidal effect during the first 2 days but not after that. Similar results were achieved when GAT was used in combination with the first line anti-TB drug INH or RIF: GAT was able to somewhat enhance the bactericidal activity of INH or RIF only for the period of the first 2 days (Paramasivan et al., 2005). This is in difference with other studies presenting that GAT and MXF had similar bactericidal effect on a stationary-phase culture of Mtb and comparable to the bactericidal effect of RIF (Hu et al., 2003; Lenaerts et al., 2005). One study reported that when evaluated in mice in combination with ethionamide and PZA (high doses: 450 mg/kg, 5 days per week). The GAT was capable to clear the lungs of infected animals after 2 months of therapy (Cynamon and Sklaney, 2003). Further research should be concentrated on to accurately evaluate the activity of GAT.
Moxifloxacin
Moxifloxacin (MXF) is the mainly capable of the new FQs being evaluated against Mtb. In-vitro, MXF show to kill a subpopulation of tubercle bacilli that not killed by RIF, while the older FQs, CPX and OFX did not have any major bactericidal effect on the same subpopulation (Hu et al., 2003). One opportunity is that MXF obstructs with protein synthesis in gradually metabolizing bacteria through a mechanism that vary from that used by RIF. In mice models the effect of MXF against tubercle bacilli was comparable to that of INH (Miyazaki et al., 1999). Furthermore, when used in combination with MXF and PZA has been kill the bacilli more successfully than the INH+RIF+PZA combination (Nuermberger et al., 2004a; Nuermberger et al., 2004b). The improved activity of the RIF-MXF-PZA combination over the RIF-INH-PZA combination as the significance of a possible synergism in the anti-TB effect of the three ant-TB drugs RIF, MXF and PZA. On the other hand, substitution of MXF with INH in the standard drug therapy could relieve a probable antagonism among the presently used drugs (Grosset et al., 1992). The MXF might be a promising candidate drug to shorten TB treatment. There is a possibility that MXF might be effective against slowly metabolizing bacteria by inhibiting DNA transcription and, therefore, mRNA and protein synthesis and having a mild sterilizing activity (Ginsburg et al., 2005; Burman et al., 2006).
New quinolone compounds
More effective quinolone derivatives that could reduce first-line treatment, different compounds have been evaluated for their anti-TB activity. The sub-class termed 2-pyridone compounds has been recognized as the most effective activity against Mtb in growing and persistant condition. These compounds have activity against drug-susceptible and DR-TB strains (Oleksijew et al., 1998). As FQ derivatives, 2-pyridones are DNA gyrase inhibitors (Flamm et al., 1995). The alterations of a position in FQ structure which influences activity, safety profile and also pharmacokinetics. The lead compounds recognized so far showed better activity than GAT and MXF.
Non-fluorinated quinolones
A series of 8-methoxy non-fluorinated quinolone analogues (NFQs), lack a 6-fluorine atom in their quinolone ring distinguishing them from fluorinated quinolone compounds such as GAT and MXF. The NFQs target a broad range of bacteria and they appear to operate preferentially through inhibition of DNA gyrase. The NFQs are presently being tested against Mtb.
Macrolides
The anti-TB effect of the macrolide antibiotics through the synthesis of additional chemically modified analogue of erythromycin. Some analogue were recognized as anti-TB agent superior to the clarythromicin (TB Alliance Annual report 2004/2005).
New rifamycin derivatives
Rifalazil, a semisynthetic RIF, is described by a long half-life and is more effctive than RIF and rifabutin against Mtb strains (Hirata et al., 1995; Shoen et al., 2000). However, high intensity RIF–resistant strains present cross-resistance to all rifamycin drugs (Moghazeh et al., 1996).
Other agents used/investigated to treat mycobacterial infections
Some β-lactam antibiotics in combination with β-lactamase inhibitors, FQs-particularly compounds that are effective in the acidic internal situation of the macrophage, clarithromycin is indicated to treat MAC infection. In an observation of the persistent DR-TB problem of currently used anti-TB drugs, it is essential that new anti-TB drug molecules should concentrated on different targets, as those of currently used anti-TB drugs including the limiting of TB therapy period. The distinctive structure of the mycobacterial cell wall makes it a valuable target for drug development and intended for to specific sites for drug action like Cell wall biosynthetic pathways (Heath and Rock 2004; Oishi et al., 1982). For example, TLM has a unique chemical structure with no chemical relation to any group of known antibiotics inhibits mycobacterial fatty acid synthase and the elongation steps of mycolic acid biosynthesis (Slayden and Barry 2002; Tripathi et al., 2005) with negligible toxicity and thus structures based on this lead or some other new molecules could provide a new class of drugs against TB. Although one possible long term solution to the problem is a better vaccine, in the short term, the major reliance will be on chemotherapy (Berning 2001) requiring the development of novel, effective and non-toxic anti-TB drugs (Pasquato and Ferreira 2001). The recognition of novel target sites will also be desirable to avoid the problems related with the increasing occurrence of MDR strains. To do this, biochemical pathways specific to the mycobacterium and related microorganisms causing disease cycle must be better understood. Many exceptional metabolic processes occur during the biosynthesis of mycobacterium cell wall components. The striking targets for the rational design of new anti-TB agents are the mycolic acids and other major components of the cell wall of Mtb (Stover et al., 2000; Tomioka and Namba 2006).
Development of new drugs for TB chemotherapy
The HIV infection offers TB more complicated to diagnose (due to higher occurrence of sputum negative disease), and treat (due to interactions and side-effects). The growing spread of MDR-TB and the intractable nature of persistent infections possess extra challenges to treatment with presently available anti-TB drugs. These situations are worsened by the rising emergence of XDR-TB (Smith, et al., 2004; Frieden, et al., 2003; Daffe, et al., 2007). Although TB can be treated, current treatment is difficult and long lasting. The DOT short course, as encouraged by the WHO to get better fulfillment for the complex and long-term regimen. Thr MDR-TB and XDR-TB is even more complex and costly to treat (Somoskovi, et al., 2001; Khasnobis, et al., 2002; Bayles. 2000). In crucial investigation, modern molecular and genetic tools have become presented for Mtb and this has led to notable progress in the information and consideration of the basic biology and physiology of Mtb strain. There are a adequate number of capable compounds for valuable new treatment combination to be developed (Teodori, et al., 2002; Glickman, et al., 2006). Furthermore, a lot of compounds are either derivatives of existing drugs or they target the same cellular development as drugs currently in uses. Even as derivatives are extreme quicker to develop, may be issue to cross-resistance, for example, RIF and quinolone derivatives (O'Brien, and Nunn. 2001). The advanced information about Mtb metabolism and physiology requests to be translated into validated targets that can be used for evaluating of new lead compounds.
MDR-TB and XDR'S implications for the TB drugs
It is critical that the new drug compounds that act by novel mechanisms which are able to target new molecular targets, in order to evade cross-resistance with drugs currently in use. In recent times, some compounds have been effective against MDR-TB and XDR-TB strains in human patients. There is an urgent requirement for new TB drugs, in order to increased the development of new drugs and hasten their delivery to patients. A most important drawback currently is the difficulty of diagnosing patients with TB (WHO. 2006; WHO. 2005). This difficulty is even more acute in the case of XDR-TB because the disease is so quickly fatal that most patients will die before the results of their diagnosis are presented. The combination of MDR-TB and XDR-TB and HIV infection leads patients to develop a highly destructive form of TB that causes death in exceptionally short time period (Asif, et al., 2011; Asif. 2011). The emergence and quick spread of MDR-TB and XDR-TB in high HIV occurrence backgrounds represent a most important threat to global health.
Table 2: Anti-TB drugs for treatment of drug-susceptible and drug-resistant TB
GroupDrugsCharacteristics
Group 1First-line oral drugss-isoniazid, rifampicin, ethambutol, and pyrazinamideThe most potent and best tolerated drugs to be used in combined 6-month therapy-each should be used if there is labs evidence and clinical history to suggest that it is effective. For patients with strains resistant to low concentrations (Conc.) of isoniazid but susceptible to higher Conc., the use of high-dose isoniazid may have some benefit (when isoniazid is used in this manner, it is considered a Group 5 drug).
New generation rifamycins-Rifabutin and rifapentineRifabutin is used in place of rifampin under certain conditions like as treatment of TB in HIV patients on protease inhibitors.
Rifapentine, a long-acting rifamycin, recommended by CDC for once-weekly continuation phase in low-risk, HIV-negative TB patients is presently in trials for treatment shortening, using higher or daily dosing.
These two newer generation rifamycins have high cross-resistance to rifampin.
Group 2Injectable agents-kanamycin, amikacin, capreomycin, and streptomycinAll patients with MDR-TB should receive a Group 2 injectable agent if vulnerability is recognized or suspected. Use of kanamycin or amikacin should be preferred, given the high rates of streptomycin resistance in DR-TB patients and the fact that both these agents are low cost, have less toxicity than streptomycin, and have been used extensively for the treatment of DR-TB globally.
Group 3Fluoroquinolones-moxifloxacin,
gatifloxacin, levofloxacin, and ofloxacinAll patients with MDR-TB should receive a Group 3 drugs if the strain is susceptible or if the agent is thought to have efficacy. The most potent available fluoroquinolones in descending order based on in vitro activity and animal studies are: moxifloxacin=gatifloxacin> levofloxacin> ofloxacin. If gatifloxacin is used, patients should undergo close monitoring and follow-up due to reports of severe dysglycaemia.
Group 4Oral bacteriostatic second-line agents- thioamides (ethionamide and prothionamide), cycloserine, terizidone, and p-aminosalicylic acidGroup 4 medications are added based on estimated susceptibility, drug history, efficacy, side-effect profile, and cost.
Group 5Agents with unclear efficacy (not suggested by WHO for routine use in MDR-TB patients)-clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, mipenem/ cilastatin, high-dose isoniazida, and clarithromycinGroup 5 drugs are not recommended by WHO for routine use in DR-TB treatment because their contribution to the efficacy of multidrug regimens is unclear. Although they have established some activity in vitro or in animal models, there is little or no evidence of their efficacy in humans for the treatment of drug-resistant TB. However, they can be used in patients in whom adequate regimens are impossible to design with the medicines from Groups 1 to 4 in consultation with an expert in the treatment of DR-TB.
CDC, Centers for Disease Control; MDR, multidrug resistant; High-dose isoniazid is 16-20 mg/kg per day
Need of new antitubercular drugs
As emphasized by the Guidelines for TB drug development (Centers for Disease Control and Prevention. 1999; Global Alliance for TB drug development. 2001) a new TB therapy should recommend at least one of the following three progresses over the presented regimens:
•Shorten the total period of treatment and/or considerably reduce the number of doses required to be taken under DOT treatment
•Improve the treatment of MDR-TB and XDR-TB
•Offered a more effective therapy of latent TB infection, limitation of the current treatment, activity against MDR-TB
•Lack of liver enzyme stimulation and inhibition (to avoid interactions with anti-retroviral drug) are the main condition for the TB Alliance is utilizing to select drug molecule that should be followed for further drug development
Table 3: Common adverse effects of drugs used for the treatment of XDR and MDR-TB and their Treatment
SubstanceCommon adverse effectsManagement
Group I
EthambutolOptic neuropathyInform the patient to report decreased vision immediately.
Discontinue and refer to an ophthalmologist if vision deteriorates
PyrazinamideHepatotoxicity, rash, gout Discontinue drug if hepatotoxicity occurs.For Rash manage symptomatically, if extensive stop drug and consider reintroduction
Group II
Amikacin, Capreomycin, KanamycinOtotoxicity, nephrotoxicityMonitor levels, hearing and renal function monthly.
If problems occur consider reducing dose frequency to three times a week.
Discontinue if problems persist, but balance risk of cure versus deafness.
Group III
Levofloxacin; MoxifloxacinGI disturbances, tendinitis, insomniaQT interval prolongation may be potentiated with other drugs
Group IV
Para-Aminosalicylic AcidNausea and vomiting, gastritis, hepatotoxicity, hypothyroidismGive antiemetics. Hypothyroidism: levotiroxine
Protionamide/
EtionamideGI disturbances, depression,
hepatotoxicity, hypothyroidismGI disturbances: initiate a stepwise approach to manage nausea and vomiting.
Start antiemetics.
Terizidone/
CycloserineNeurotoxocity, peripheral neuropathyGive high dose pyridoxine, up to 50 mg for every 250 mg of drug.
If neuropathy progresses discontinue drug. Discontinue if psychosis develops.
Seizures can be amanaged with anitconvulsants but drug may ned to be discontinued.
Group V
Amoxicillin/Clav. AcidHypersensitivity, GI disturbancesFor serious allergic reactions, stop all therapy pending, resolution of reaction.
ClofazimineSkin discolouration, GI disturbances-
Imipenem, MeropenemHypersensitivity, neurotoxocityMonitor blood count
LinezolidNeuropathy, anaemiaMonitor blood count, avoid prolonged use. Stop if peripheral neuropathy or hematological problems occur.
Isoniazid (high dose)Peripheral neuropathy, hepatotoxicityGive with pyridoxine
Anti-TB with new and different moiety
In order to reduce the development time for a new drug regimen, TB alliance is working on both recognizing individual new compounds and developing new drug combinations. In order to investigating useful drug candidate currently in two major categories: Novel chemical entity and compounds instigating from existing relatives of currently used drugs, where novel chemistry is used to optimized the new compounds. The current concepts and processes of drug discovery and devel¬opment. Several approaches, such as genome-derived, target-based approaches, phenotypic screens at a whole bacterial cell level, multi-target “pathway” screens and redesign existing scaffolds have been utilized for newer anti-TB drug discovery. Presently, several newer drugs are in pipeline in various stages of development as anti-TB drugs.
Nitroimidazopyrans and nitroimidaoxazoles derivatives
In this series, the lead molecules are CGI 17341 and PA824/PA1343. The target enzyme for the drug molecules has been concerned in cell wall synthesis (Ashtekar, et al., 1993). Further investigation is to try and recognize more effective molecules. However, two key areas of concern also require to attend-possible mutagenicity resulting from the presence of a nitro group, and the chance for the development of drug resistance. The latter is encouraged by the reality that the nitroimidazoles induce a high rate of mutation (Stover, et al., 2000), leading to uncertainties that this might cause the appearance of MDR bacteria. Since the drugs will certainly be used in combination therapy.
Nitroimidazole PA-824
The nitroimidazole PA-824 is a new nitroimidazole derivative for the treatment of TB. After activation by a mechanism dependent on Mtb F420 factor, PA-824 acts mostly by inhibiting the synthesis of cell wall components by molecular targets that are yet to be recognized. In vitro, PA-824 exhibited high activity against drug-sensitive and MDR-TB strains, representing that there is no cross-resistance with existing TB drugs. Moreover, PA-824 is displayed invitro bactericidal activity against both replicating and static bacteria (Stover, et al., 2000). The PA-824 bactericidal action against non replicating bacteria was equivalent to that of RIF (Lenaerts, et al., 2005). The PA-824 at doses ranging from 25 to 100mg/ml exhibited decreased bacterial burden in spleen and lungs of mice. Although PA-824 was considerably more competent than INH or moxifloxacin in clearance the infection during the extension phase, it was not superior than that of RIF and INH combination (Tyagi, et al., 2005). In long-term treatment performed to find out its sterilizing capacity, administration of PA-824 as monotherapy in mice led to reduced in bacterial counts in the lungs as good as to that obtained with RIF or INH monotherapy. After 12 weeks of management with PA-824, RIF or INH, an entire abolition of the bacterial load was not attained in any of the treated mice (Lenaerts, et al., 2005). When a 6-month treatment therapy containing PA-824 in combination with RIF, INH and PZA was evaluated in mice, any of the PA-824 containing therapy resulted better to the standard first line anti-TB regimen in terms of more rapid reductions of the bacterial load during therapy and lower rates of relapse after treatment (Nuermberger, and Grosset. 2004). Further exploration are essential to evaluated the potentiality of PA-824 to get better the treatment of both drug-susceptible and MDR-TB. PA-824 entered in clinical trials.
The enzyme dihydro lipoamide acyltransferase (dlaT) is act as an effective target for the chemotherapy of Mtb. The Mtb dlaT is a constituent of two essential multi-subunit complexes: pyruvate dehydrogenase, the enzyme that catalysis the synthesis of Acetyl Coenzyme A, and peroxynitrite reductase, a defence against oxidative or nitrosative stress (Tian, et al., 2005). The DlaT has been exhibited to be required for full virulence in vivo in mice, while in in vitro test mouse macrophages can eagerly kill intracellular Mtb mutants lacking dlaT (Shi, and Ehrt. 2006). These compounds are active against specific distinct molecular targets, including inhibitors of DNA gyrase, peptide deformylase (PDF) inhibitors and derivatives of quinolone electron transport inhibitors. Bacterial peptide deformylase goes to a subfamily of metalloproteases catalysing the removal of the N-terminal formyl group from recently prepared proteins. The PDF is necessary for bacterial growth but is not necessary by mammalian cells, so signified a promising target for the advance of a new generation of all-purpose antibacterial agents. The PDF inhibitors are VIC-104959 (LBM415) and BB-83698 (Jain, et al., 2005). The PDF inhibitor BB-3497 was newly found to have effective in vitro activity against Mtb (Cynamon, et al., 2004). This result proposed that PDF inhibitors can discover application in TB treatment. Recently, anti-TB drugs targeting ATP synthesis have been exhibited for predominantly effective, even against non-replicating bacteria.
Nitroimidazoles CGI 17341
The Ciba-Geigy 5-nitroimidazole derivative CGI 17341 showed considerable potential for the management of TB in preclinical study. In vitro at 0.04 to 0.3µg/ml the compound inhibited both drug- susceptible and MDR strains of Mtb and exhibited no cross-resistance with INH, RIF, SM or EBM. Against Mtb in-vitro, its action was comparable to that of INH and RIF and higher to SM, norfloxacin, ciprofloxacin and the oxazolidinone DuP 721. In Mtb-infected mice, oral therapy with CGI 17341 on days 11 and 12 after infection resulted in an ED50 of 7.7 mg/kg and a considerable dose-dependent enhance in survival time (Ashtekar, et al., 1993). In a recovery of attention into the 5-nitroimidazoles, a series of nitro imidazopyran compounss has been recognized for the treatment of TB. These agents were not mutagenic and showed potent bactericidal activity against replicating and static Mtb, including MDR strains.
Nitroimidazole OPC-67683
It is mycolic acid inhibitors and interferes with the biosynthesis of the mycobacteria cell wall. The MICs value of this compound was determined by using standard and clinically isolated Mtb strains, including MDR-TB strains. In vitro, OPC-67683 was exhibited high activity against drug-sensitive as well DR strains with MICs varing 6-24 ng/mL. There is no cross-resistance with any of the current first-line anti-TB drugs was observed. Moreover, OPC-67683 exhibited strong intracellular activity against H37Rv strain of Mtb residing within human macrophages and type II pneumocytes. The OPC-67683 is active against MtbH37v and MDR-TB strains in-vivo starting from a concentration of 0.03125 mg/body.
PA-824CGI 17341OPC-67683
The OPC-67683 exhibited 6-7 fold elevated activity compared to first line drugs INH and RIF. There is no antagonist action could be observed when OPC-67683 was utilized in combination with presently used anti-TB drugs in-vivo. The bioavailability in each species was 35-60% with a concentration 3-7 times more in the lung than in the plasma. The compound was well dispersed in most tissues.
Imidazole analogues
It remains to be established whether the in vitro effects of miconazole result from the presence of a pharmacophore shared by the rest of the anti-fungal azoles or whether they are unconnected and the antimicrobial properties result from other structural features. This can readily be ascertained by screening a selection of the anti-fungal drugs. Miconazole is a well-known antifungal drug which has been accounted to have anti-TB activity in vitro against Mtb H37Ra (MIC 2µg/ml). The potency of the compound is inhibiting replicating bacteria, it also has some effect on stationary phase bacilli (Sun, and Zhang. 1999). Unfortunately, miconazole is not active orally and therefore is little additional interest for progrressing a TB indication (Groll, and Walsh. 1997).
1,2,4-Triazoles
Various 1,2,4-triazoles have been estimated against Mtb H37Rv. Compound (1) gave 61% inhibition at 6.25 µg/ml (Hudson, et al., 2003). Other triazole analogues were inactive.
Imidazo (4,5-c)pyridine compounds
From a series of imidazo (4,5-c)pyridines, one compound (2) for common formula (R1, R2 unrevealed)-inhibited Mtb H37Rv and other strains with MICs range 0.256-2.56µg/ml. Imidazo (4,5-c)pyridines were initially prepared as anti-mitotic agents for cancer therapy but in the present work, less cytotoxic agents were chosen and found to have anti-TB activity (Hudson, et al., 2003).
Diarylquinoline compounds
Diarylquinolines (DARQs) are structurally unlike from both FQs and other quinolines derivatives. The DARQ R207910 is a part of a new chemical class of anti-TB drugs and has MIC value equal to or lower than reference drugs. It has specificity towards mycobacteria as well as atypical species, important in humans such as MAC, M. kansai, and the fast growing M. fortium and M. abscessus (Shindikar, and Viswanathan. 2005). The anti-TB specific spectrum differs from that of INH, which has very poor activity against MAC. The use of this will be extremely targeted to the treatment of the TB infections, mainly targeting the proton pump of ATP synthase (Andries, et al., 2005).
Diarylquinoline TMC207
Diarylquinoline (DRQ) TMC207 is an exceptionally promising component of a new class of anti-TB drugs. About, 20 compounds of the DRQ series have been exhibited a MIC value below 0.5μg/ml against Mtb H37Rv and in-vivo antimicrobial activity of these compounds (Andries, et al., 2005). The most active compound of this class is TMC207 and its range is exclusive in its specificity to Mtb. The target and mechanism of action of DRQ TMC207 is different from those of other anti-TB compounds involving low probability of cross-resistance with accessible anti-TB drugs. The DRQ TMC207 is capable to inhibit bacterial growth when evaluated on MDR-TB isolates and appears to act by inhibiting the ATP synthase (Petrella, et al., 2006), most important to ATP depletion and pH imbalance. Moreover, DRQ TMC207 has effective late bactericidal activity in the well-known infection in murine TB model. Substitution of RIF, INH or PZA with DRQ TMC207 hasten activity leading to complete culture conversion after 2 months of therapy in some combinations. The DRQ TMC207 has been also evaluated in different combinations with the second line drugs amikacin, PZA, MXF and ethionamide in mice infected with the drugs susceptible virulent Mtb strain H37Rv (Dolezal et al., 2003).
Purine analouges
The 9-Benzylpurines, with a variety of substituents on 2, 6 and/or 8 position, have been shown to possess high inhibitory activities against Mtb. One of the compounds, carrying trans-styryl or aryl substituents at 6 position and generally chlorine in 2 position tends to increase the activity and has MIC of 0.78mg/mL in vitro (Bakkestuen, et al., 2000). Anti-TB activity of 6-arylpurines (Gundersen, et al., 2002) and 9-sulphonylated or sulphenylated-6-mercaptopurines are also known (Scozzafava, et al., 2001).
Benzylpurines
A series of 9-benzylpurines, 2-chloro-4(2-furanyl)-9-benzylpurine was shown to potently inhibit Mtb H37Rv in-vitro with a MIC value of 0.78µg/ml. It exhibited low cytotoxicity towards VERO cells (IC50 value-8.1µg/ml)–selectivity index (MIC/IC50) of 10.4.
Thiolactomycin Analogues
Naturally occurring (5R)-thiolactomycin (TLM) exhibits potent in vivo activity against many pathogenic bacteria, including Gram-negative and Gram-positive bacteria and Mtb (Miyakawa, et al., 1982). TLM inhibits bacterial and plant type II fatty acid synthases (FAS-II) but not mammalian or yeast type I fatty acid synthases (FAS-I) (Hayashi, et al., 1983). In Escherichia coli, it inhibits both β-ketoacyl-ACP synthase I to III and acetyl coenzyme A (CoA): ACP transacylase activities (Heath, et al., 2001; Tsay, et al., 1992). The TLM was the first example of naturally occurring thiolactone to displayed antibiotic action. The TLM analogues have been synthesized and established to have improved activity against whole cells of pathogenic Mtb strains (Douglas, et al., 2002). The TLM analogues appear to act by the inhibition of the mycolate synthase, an enzyme concerned in the biosynthesis of the Mtb cell wall. The TLM inhibits bacterial as well as plant type II fatty acid synthases (FAS-II), which provide essential building blocks for the bacterial cell wall. TLM is believed to exert its overall effect by inhibition of the β-keto acyl-ACP-synthases (Kas), key condensing enzymes involved in the chain elongation in FAS-II. TLM is an antibiotic of considerable attention because of its selective action in disrupting essential fatty acid production in bacteria, plants and some protozoa, not in eukaryotes. This has lead to hope that inhibitors of the TLM target enzyme, FAS-II, are of potentially important in the treatment of malaria (Waller, et al., 1998), trypanosomiasis or sleeping sickness (Morita, et al., 2000) and a range of bacterial indications including TB. The TLM is a selective inhibitor of the mycobacterial acyl carrier protein-dependent type-II fatty acid synthase (FAS-II) but not the multifunctional type-I fatty acid synthase (FAS-I) present in mammals. It also blocks long-chain mycolate synthesis in a dose-dependent mode (Slayden, et al., 1996). The principal mode of action of INH is also interruption of mycolic acid synthesis, but there is no cross-resistance among the two molecules. This is because INH requires activation by a katG catalase-peroxidase enzyme and in various resistant strains of Mtb. This enzyme is mutated and unable to change the drug to its active species (Johnsson, and Schultz. 1994). Therefore, TLM is active in vitro against extensive range of strains of Mtb, including INH- resistant, although at somewhat high concentrations. For example, complete inhibition of growth on solid media of the powerful strain Mtb Erdmman is seen at 25µg/ml. The progression of TLM itself as an anti-TB agent (Chambers, and Thomas. 1997) and racemic mixtures, e.g. compounds (A) and (B), which are accounted to have superior activity than the parent in inhibiting Mtb H37Rv in vitro.
Thiolactamycin(A)(B)
Mefloquine analogues
MefloquineWR-3016WR-3017
The antimalarial agent mefloquine (a 4-aminoquinoline methanol), and its various analogues have activity against a range of bacteria including Mtb (Kunin, and Ellis. 2000). A series of quinolinemethanol analogues, two compounds, WR-3016 and WR-3017, exhibited potent inhibitory effects in vitro in the M. avium complex-1 (MAC) assay with MIC50 values of 1 and 2 µg/ml respectively, compared to 16µg/ml for mefloquine (Hudson, et al., 2003). Other mefloquine analogues, two enantiomers of mefloquine and might be valuable to test some representative 4-aminoquinoline antimalarials such as chloroquine (De, et al., 1998). There is also attention in the anti-TB property of the mefloquine analogue desbutylhalofantrine (3). This compound is in progress for its antimalarial activities with advantage over the parent drug halofantrine of lesser cardiotoxicity (3).
Deazapteridines
From a series of 2,4-diamino-5-deazapteridine derivatives, SRI-20094 exhibited potent inhibition of MM6 cells infected with M. avium complex strain NJ3440 with an MIC of at most 0.13 mcg/ml. SRI also confirmed outstanding inhibition of dihydrofolate reductase (DHFR) of the M. avium complex, with an IC50 value of 1.0 nM as compared to 4100, 1.0 and 1.4 nM for the known drugs trimethoprim, trimetrexate and piritrexim. It showed limited inhibition for human DHFR having an IC 50 value of 7300 nM. SRI-20094 is a possible value for the infection of M. avium and, in particular, for persons co-infected with HIV. Other close analogues were highly active against Mtb with MICs of ~0.1mg/l (Li, et al., 2004).
1,2,4-Benzothiadiazines
Sulfonamides are well known for their antibacterial property and a large number of such compounds have been developed as antimicrobial agents. The 1,2,4-benzothiadiazine dioxides have a close relation to sulfonamide and could be considered as cyclic sulfonamide class of molecules. These compounds are well known for a variety of biological properties, including antimicrobial activity (Dolezal, et al., 2003; Cocco, et al., 1999). The 1,2,4-benzothiadiazine system was explored by incorporating other heterocyclic rings like pyridine and pyrazine moieties (4 and 5). Some molecules based on 1,2,4-benzothiadiazine system that exhibited interesting anti-TB activity (Kamal, et al., 2007; Kamal, et al., 2006). Some molecules based on 1,2,4-benzothiadiazine system that exhibited interesting anti-TB activity.
Other molecules
Several other molecules like pyrroles (6) (Deidda, et al., 1998), quinoxaline-1,4-dioxides (7) (Jaso, et al., 2005) and alkylsulfinyl amides (8) (Jones, et al., 2000), etc. have also been prepared and tested for their anti-TB activity. Recently some new targets such as signaling kinase inhibitors have been investigated. The survival of Mtb against the macrophage phagocytosis relies not only on a thick cell wall but also on many mycobacterial kinases and phosphatases which disrupt the host-cell defence mechanism against parasitism (Koul, et al., 2004; Scherr, et al., 2007; Soellner, et al., 2007). Histidine kinase is the focus for the specific inhibition of two component signal transduction system in Mtb (Stephenson, et al., 2000; Stephenson, and Hoch. 2004). Based on this signal transduction system, a series of anti-TB salicylanilides and related compounds have been reported (Matyk, et al., 2005; Waisser, et al., 2006). Inhibition of this type of regulation has been involved in the virulence of Mtb in mice. Eleven putative eukaryotic–like protein serine-threonine kinases (Pkn A to L) involved in signal transduction have been identified in Mtb H37Rv genome (Av-Gay, and Everett. 2000). Based on this kinase inhibition benzothiophenes (specifically inhibits Pkn G) (Walburger, et al., 2004; Koul, et al., 2005) and benzoquinoxalines (inhibitors of Pkn B, Pkn G, and Pkn H) (Pato, et al., 2004; Zanetti, et al., 2005) have been reported. Hence the research on signaling kinase inhibitors could also provide target oriented lead molecules for the control of TB. In analysis of the constant MDR-TB problem, new drugs should concentrate on different targets, including the reduction of TB therapy (Heath, and Rock. 2004), with negligible toxicity and thus structures based on this lead could provide a new class of antibiotics against TB.
(4)(5)
R= Me, Et, i-Pr, PhR= Me, Ph
R1= H, ClR1= H, Cl
X=CH, NX= CH, N
Y= CH, NY=CH, N
Z=CH, N, CClZ= CH, N, CCl
Benzoxazines
(9)(10)
A series of 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 6-chloro-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones, revealed compounds (9) and (10) to have potent anti-TB activity against Mtb (MIC values 0.5 mcmol/l), M. kansasii (2 and 2 µmol/l), M. avium (16 and 16 µmol/l) and M. kansaii (1 and 0.5 µmol/l), compared with MIC values of 4, 8, 500 and 500 µmol/l for INH after 14 days (Hudson, et al., 2003).
Diterpenoids
PseudopteroxazoleSeco-pseudopteroxazole(11)
Evaluating marine natural products gorgonian coral Pseudopterogorgia elisabethae from the West Indian for anti-TB activity resulted in the isolation and recognition of two active diterpenoid alkaloidal compounds, seco-pseudopteroxazole and pseudopteroxazole. Both compounds are new diterpenoids having the unusual benzoxazole group (Rodriguez, et al., 2001). The pseudopteroxazole against Mtb H37Rv was claimed to be a powerful inhibitor giving 97% growth inhibition at 12.5µg/ml even as secopseudopteroxazole was rather less active. A number of of these, are significantly more active than the marine diterpenoids (11) with MIC value of Mtb H37Rv = 0.46µg/ml. Such compounds, even though still novel, look like structurally more agreeable to analogue synthesis.
Tryptanthrin derivatives
Tryptanthrin R=H, X=CH and PA 505, R=CH (Me)(CH2)5Me, X=N
Tryptanthrin is a structurally new indoloquinazolinone containing alkaloid and was first isolated by Chinese scientists, which has been evaluated against different strains of Mtb including drug-sensitive strain of Mtb H37Rv. The MIC value of tryptanthrin was 1.0 µg/ml compared to MIC value of INH was 0.03µg/ml. When evaluated against a section of MDR-TB strains, even as tryptanthrin sustain its effectiveness (MICs of 0.5-1µg/ml), INH had declined activity with MIC value 4-16µg/ml. Many derivatives of this lead structure have been tested for their potential in TB treatment. For example, PA-505 having powerful in vitro activity towards Mtb H37Rv-MIC 0.015µg/ml and had only modest actions in reducing Mtb in the spleen of infected mice when given orally at 50mg/kg/day for ten days (Mitscher, and Baker. 1998).
Clofazimine or tetramethylpiperidino (Tmp) phenazines analogues
The tetramethyl piperidine substituted phenazines B4169 and B4128 (TMP phenazines) have been found to possess significantly more activity against Mtb, including MDR clinical strains than clofazimines (Field, and Cowie. 2003). Recently, new conjugates of phenazine with phthalimido and naphthalimido moieties have been designed as anti-TB compounds (Kamal, et al., 2005). Some compounds of phenazine class, these phenazine hybrids have shown potential results in the inhibition of Mtb ATCC 27294 as well as their clinical isolates (both sensitive and resistant). There is a prospective to design such type of phenazine hybrids for the expansion of new anti-TB agents. New phenazine conjugates with naphthalimido and phthalimido moieties (12) have been designed as anti-TB agents. Some of the compounds of this novel phenazine class have shown potential results in the inhibition of Mtb ATCC 27294 and their clinical isolates. This study discovered that there is a potential to design new phenazine hybrids for the research and development of new anti-TB agents (Kamal et al., 2008).
,
12n = 0, 1, 2, 3
ClofazimineB4169B4128
The anti-TB effcets of a series of new tetramethyl piperidinophenazine compounds closely associated to the anti-leprosy drug clofazimine. The intra- and extracellular effects of these compounds were compared to anti-leprosy drug clofazimine and RIF against Mtb H37Rv. One of the phenazine compounds, B4169, effectively inhibited the bacterium with an MIC value of 0.015µg/ml; the equivalent value for clofazimine was 0.06µg/ml. These compounds were more active than clofazimine against a series of clinical Mtb isolates plus MDR-TB strains. In addition some of the phenazine derivatives, e.g. B4128, exhibited significant intracellular activity (~60% inhibition of growth) at 0.001µg/ml against Mtb infected monocyte derived macrophages and were better to both clofazimine and RIF drug. Since they have close structural resemblance to clofazimine, most probable they will suffer from the unwanted effects of the imparting noticeable coloration to the skin of patients (Hudson, et al., 2003).
Phenazine B4157
The B4157 is a phenazinamine analogue, closely associated to the anti-leprosy drug clofazimine, which has been examined as a potential action for TB. In vitro, clofazimine and B4157 were evaluated against 20 strains of Mtb, with 16 drug-resistant strains, and all were found to be vulnerable to B4157 including one which demonstrated reasonable resistance to clofazimine. The MICs of B4157 and clofazimine at which 90% of strains were inhibited was 0.12 and 1.0 µg/ml. Though, against Mtb in C57BL/6 mice at 20 mg/kg, clofazimine was slightly superior to B4157 (Hudson, et al., 2003).
B4157(13)
Toluidine derivatives
Some simple analogues of toluidines have shown attractive in vitro activity against Mtb 103471, the best compound represented by (14), having MICs values 4 µg/ml-cf MICs of INH, 0.25µg/ml, and SM, 0.5µg/ml. However, these aromatic amines will undergo rapid metabolic degradation, possibly to toxic metabolites (Hudson, et al., 2003).
Saccharides
SR-9581(14)
The arabinose disaccharide SR-9581 is effective in vitro against Mtb, with a MIC value is 4µg/ml. It reduced the viability of Mtb by 76.1%, 97.8% and 99.9% at 8, 16 and 32 µg/ml respectively in 3 days. In a study (Ramneatu, et al., 2000), other saccharide, an arabinofuranoside oligosaccharide (14), is maintained to be a substrate for mycobacterial arabinosyltransferases. Both compounds can be anticipated to disrupt Mtb cell wall biosynthesis (Bertino et al., 2000).
Oxazolidinones (linezolid)
The Oxazolidinones are a novel class of broad-spectrum antibiotic compounds. They inhibit protein synthesis through binding to the 50S subunit of ribosomes. Oxazolidinones had considerable activities against Mtb in-vitro in mice (Cynamon, et al., 1999). However, oxazolidinones are observed as less promising due to their toxicities and high cost value. However, far less information is in the public domain as to the likely toxicities of these agents (Brickner, et al., 1996; Eustice, et al., 1988; Field and Cowie 2 003).
Oxazolidinones PNU 100480 and AZD 2563
The oxazolidinone derivatives are the potential new class of synthetic antimicrobial compounds with a distinctive mechanism of action in inhibiting protein synthesis (Diekema, and Jones. 2000). In common they demonstrated that bacteriostatic activity against various important human pathogens together with drug-resistant microorganisms (Corti, et al., 2000). The oxazolidinone compounds have activity against Mtb and compound linezolid (U-100766) inhibiting MDR isolates in vitro at 2µg/ml (Zurenko, et al., 1996). Oxazolidinones containing a thiomorpholine group in place of the morpholine group present in linezolid have been accounted to be predominantly active against Mtb with MICs of 0.125µg/ml (Barbachyn, and Brickner. 1996). One compound of this series, compound PNU-100480, was evaluated in a murine model against ten practicable strains of Mtb in comparison to linezolid and INH. PNU-100480 established equivalent to INH and more active than linezolid (Cynamon, et al., 1999).
Calanolides
Calanolide A is a naturally pyranocoumarin of considerable attention because of its double action against TB and HIV infections (A New Drug to treat Tuberculosis: 2000). This compound is an inhibitor of HIV-1 reverse transcriptase enzyme (Hudson, et al., 2003). It also exhibits good in vitro effects towards Mtb. In a beginning evaluation of its activity, calanolide A was analogous to the positive control INH and staying effective against RIF and SM resistant TB strains. Calanolide A thus decreasing the dependency upon acquiring the material from limited natural resources (A New Drug to treat Tuberculosis: 2000) and some compound, e.g. (15), have been patented for their anti-TB activities. Calanolide B, which distinct calanolide A, is existing in considerable quantities from renewable natural sources, e.g. from Calophyllum seed oil, (Spino, et al., 1998) have a similar range of activity to calanolide A against Mtb and may be an additional cost-effective treatment.
Poloxamer 315 (CRL-1072)
Poloxamer 315 is a methyloxirane surfactant polymer that shows to disrupt the cell membranes of microrganisms or their intracellular components. The extremely purified polymer has been shown to be effective against Mtb and M. avium. In vitro effect against Mtb in broth culture medium showed MIC values 3.1-6.2µg/ml even as, in a macrophage assay, these go down to 0.92 to 1.25µg/ml. This compound was effective against strains of Mtb resistant to INH, SM and RIF (Jagannath, et al., 1995).
Calanolide ACalanolide B(15)Niclosamide
Niclosamide
The anthelmintic drug niclosamide was found to have anti-TB activity in vitro (MIC 0.5-1µg/ml) against Mtb H37Ra. As well as being active against growing cells, it has the interesting property of acting against stationary phase non-replicating bacterial cells. However, niclosamide has been useful for the treatment of human tapeworm infections, it is not absorbed to any significant extent from the intestine (Cruthers, et al., 1979).
Mikasome
Amikacin is an aminoglycoside used as a second-line anti-TB drug. The liposome-encapsulated drug for development of anti-TB activity, MiKasome, has been found to be useful against M. avium infections in vitro and in animal models (Hudson, et al., 2003). In animals, information illustrated that MiKasome formed 7-fold higher peak plasma levels compared to free drug amikacin (i.v.). The AUC was 150-fold higher with the liposomal substance and a single dose of liposomal amikacin formed therapeutic levels of antibiotic for more than 72 hr. The pilot Phase II studies revealed that MiKasome was capable to resolve Mtb infections who had failed conventional therapies.
Fulleropyrrolidines
A series of fullerene analogues, compound (2.158) exhibited anti-TB activity. It inhibited the growth of a human clinical isolate, Mtb strain H6/99, with a MIC value of 5 µg/ml and strain H37Rv with a MIC value of 50µg/ml (Hudson, et al., 2003). Some fullerene compounds have also revealed in-vitro activity against the HIV protease contribution the tantalising possibility of combined effectiveness towards both AIDS and TB. However, the occurrence of the quartenary nitrogen atom proposed that toxicity matters might be a difficulty.
Pyrrole LL- 3858
Pyrroles analogues were originated to be effective in-vitro against standard and drug-sensitive Mtb strains (Deidda, et al., 1998; Ragno, et al., 2000). The pyrrole compounds (LL-3858) exhibited higher bactericidal effect than INH when given as monotherapy to infected mice. In mice models, a 12 weeks treatment with LL-3858 in addition of INH and RIF, or LL-3858 plus INH-RIF-PZA, sterilized the all infected lungs of mice.
Dipiperidine SQ-609
Dipiperidine SQ-609 is a new compound structurally dissimilar to existing anti-TB drug. It destroyed Mtb by interfering with cell wall biosynthesis (exact mechanism unknown). Antimicrobial effect has been established in vivo in mice models (Nikonenko, et al., 2004; Kelly, et al., 1996).
Pleuromutilins
The pleuromutilins is a natural product and a novel class of antibiotics. They interfere with protein synthesis by binding to the 23S rRNA and consequently inhibiting the formation of peptide bond (Schlunzen, et al., 2004). The cross-resistance might happen between pleromutilins and oxazolidinones (Long, et al., 2006). Pleuromutilins have been revealed to in-vitro inhibition of the Mtb growth. The pleuromutilin compound is active against MDR-TB and permited shortening of the treatment time (Global TB Alliance Annual report 2004-05).
ATP synthase inhibitor FAS20013
The FAS20013 is a new compound and belongs to the class of ß-sulphonylcarboxamide analogues. FAS20013 destroy more organisms in a 4-hour exposure than INH or RIF can throughout a 12- to 14-day exposure. This compound is especially effective in killing of MDR-TB organisms that are resistant to currently used multiple drugs. The greater effect of FAS20013 compared to current anti-TB drugs in terms of its ability to sterilize TB injuries and kill latent TB strains. Therapeutic estimation of FAS20013 has continually revealed its efficiency in mice with no serious adverse effects. This compound is up to 100% bioavailable when orally administered. The compound is consideration to act through inhibition of enzyme ATP synthase (Global TB Alliance Annual report 2004-05; Jones et al., 2000; Parrish, et al., 2004).
Diamine SQ-109
Diamine SQ-109 has been identified in a showing and using a combinatorial library based on the lead drug EMB. The plan was to develop a second-generation drug molecule from the first line anti-TB drug EMB. When evaluated in mice using a low-dose infection model of TB, SQ-109 at 1 mg/kg was as efficient as EMB at 100 mg/kg. However SQ-109 did not exhibited improved efficiency at higher doses (10mg/kg; 25mg/kg) and was evidently less effective than INH (Protopopova, et al., 2005). The SQ-109 is effective against MDR-TB, together with those that are EMB-resistant, and that it targets different intracellular targets. For this reason it can be considered as a new TB drug and not basically as an EMB derivative.
Nitrofuranylamides
(2.158)Pyrrole LL- 3858(16)
The Mtb is relatively vulnerable to Nitrocontaining compounds (Murugasu-Oei, and Dick. 2000). Nitrofuranylamide (16) was recognized in a screening for UDP-Gal mutase inhibition. A prolonged set of nitrofuranylamides was tested for anti-microbial activity. This led to the recognition of a number of nitrofuranylamides with activity effective against Mtb (Tangalapally, et al., 2005; Tangallapally, et al., 2004).
Table 4: Newer and repurposed anti-TB drugs in pipelines (WHO 2011; Yew. 2009; Sharma and Sarkar. 2018; Sanyaolu et al., 2019)
Drugs in preclinical developmentDrugs in clinical development
Phase IPhase IIPhase III
Nitroimidazole
TBA-354
Caprazene nucleoside
CPZEN-45
Fluoroquinolone
Quinolone DC-159a
Dipiperidine
SQ609
Capuramycin
SQ641
Benzothiazinone
BTZ043
Imidazopyridine
Q201
Mepenzolate bromide
SPR-10199Oxazolidinone
AZD5847Nitroimidazole oxazine
PA-824
Oxazolidinone
Sutezolid (PNU-100480)
Linezolid
Diarylquinoline
Bedaquiline (TMC207)
Ethylenediamine
SQ109
Rifamycin
RifapentineFluoroquinolones
Gatifloxacin
Moxifloxacin
Nitro-dihydro-imidazooxazole
Delamanid (OPC67683)
4-Thioureido-iminomethylpyridinium Perchlorate
Perchlozone
Vaccines for tuberculosis
In recent years, there is an increasing trend of MDR-TB and worldwide about 480,000 people developed MDR-TB in 2013. Among MDR-TB patients, 9% were diagnosed with XDR-TB (Thomas. 2008; WHO. 2014). Some cases with total drug resistance (TDR-TB) to first and second line anti-TB drugs have also been reported (Velayati, et al., 2013). Immuno-compromised individuals, especially HIV-infected patients, are more prone to TB infection. The Joint United Nations Programme on HIV and AIDS (UNAIDS) estimated that among 2.6 million new cases of HIV infection, 1.8 million were associated with TB (WHO. 2013). According to the WHO, Asia region has been most severely affected by TB. The burden of TB in South-East Asia and Western Pacific Regions together accounts for 58% of total TB cases worldwide in 2012. Among top five countries with the high burden of incident cases, India ranked first (2.0 million) followed by China (0.9-1.1 million), South Africa (0.4-0.6 million), Indonesia (0.4-0.5 million) and Pakistan (0.3-0.5 million) (WHO. 2013). Following this re-emergence and DR trends, the WHO was forced to declare TB as a global public health emergency during 1993 (MAPTB. 2014; Ottenhoff and Kaufmann. 2012). The numbers of DR-TB cases are increasing. The spectrum of resistance varies from single to multidrug and from multidrug to total drug resistance varieties. The HIV infection is also responsible for the current re-emergence of TB worldwide. When drugs are becoming ineffective against Mtb, there is a need to focus more on preventive approaches. Though Bacillus Calmette-Guérin (BCG) vaccine is well-organized in preventing miliary and meningeal TB in children, it is not effective against pulmonary TB. For prevention of pulmonary TB, advance of new vaccines is the need of time. Several new vaccines are under clinical trials either to replace old BCG or act as a booster for the current BCG vaccine. New vaccines include live Mycobacterial vaccines, its subunit, live vector-based vaccines and killed whole or fragmented vaccines (Sumera et al., 2016).
Previous old BCG vaccine
The only vaccine that was available for TB till date is the M. bovis Bacillus Calmette-Guérin (BCG) vaccine, isolated by Calmette and Guerin in Lille, France (Charles, et al., 2013). This vaccine was first used to a human infant in 1921. Since then more than 100 million of BCG vaccines are used to infants yearly. It is well-known fact that BCG can protect the infant from meningeal and miliary TB. However, the efficiency of BCG vaccine in preventing TB is reduced in old age group.
Limitations of BCG vaccination
Though BCG can prevent meningeal and miliary TB in infants, it cannot provide immunity in adults to prevent pulmonary TB. This vaccine also cannot be used to HIV-infected children. Studies have revealed that when BCG was given to children who were infected with HIV, there was a high risk of developing systemic or disseminated TB (Hatheril. 2011). The Global Advisory Committee on Vaccine Safety has already issued warning that HIV-infected infants should not be given BCG injection (Global Advisory Committee on Vaccine Safety, 2007). Another limitation of BCG is that it does not provide protection against reactivation of LTBI (Mack, et al., 2009). Researchers are still explored the reasons that why BCG vaccine is unable to prevent pulmonary TB in adolescents. The present BCG vaccine has lost more than 100 genes in regions of difference (RD) from its original genome (Hess and Kaufmann. 1999; Montañésa and Gicquel. 2011). Helminth infestations are also connected with increased incidence of TB by interfering with the protective anti-TB responses (Svenson, et al., 2010) and affect the immune responses by inducing Th 2 or increased regulatory T-cell (Treg) activity (Kaufmann, et al., 2010).
Role of new vaccines
Limitations of the old BCG vaccine have urged the scientists to develop new effective vaccines in preventing tuberculosis. The primary goal of the new vaccines is to provide immunity to TB for all age groups and also in patients with HIV (Hatheril. 2011). Some of the vaccines in clinical trials are designed to be safer in HIV-infected individuals (McShane, 2011; Hesseling, et al., 2007). The new TB vaccine also needs to be safe, stable, inexpensive and should be able to provide long-lasting immunity (Andersen, 2011). Another role of new TB vaccine is its ability to combine with other vaccines that are given in childhood. This is because the large percentage of the world population is infected with Mtb. Thus, a booster is also required to protect against various types of Mtb infections. A new BCG vaccine booster with minimum 50-70% efficacy can save about one-quarter of the TB population (Svenson, et al., 2010).
New vaccines for TB
The aim of developing new TB vaccines is either to replace the old BCG or act as a booster for the current BCG vaccine. The new TB vaccines that are being undergone clinical trials can be differentiated into a viral vector, subunit, bacterial vector and heat-inactivated Mycobacterium (Andersen, 2011).
Live mycobacterial vaccines
The development of new TB vaccines is either to improve the recombinant (r) BCG or to acquire a more efficient and genetically attenuated Mtb to be used to prevent TB (Ottenhoff and Kaufmann. 2012; Montañésa and Gicquel. 2011). In rBCG is the recombinant strain of BCG that uses BCG as a backbone to express T-cell immunity from Mtb (Cayabyab, et al., 2012). In rBCG, antigens can act together to maximize the protection and at the same time, researchers expect rBCG to have a prolonged life time in the tissues thus ensuring the immunological memory (Andersen, 2011). To construct rBCG, immunodominant Mtb-specific antigens i.e. RDI and RD2 loci are introduced into BCG (Montañésa and Gicquel. 2011). A study shows that the ESX-1-complemented BCG vaccine provided better protection than BCG against TB (Bottai, et al., 2015). The rBCG30 is engineered for over-expressing the gene Ag85B. This antigen is a protein that secreted by Mtb (Cayabyab, et al., 2012). It is found that rBCG30 secretes more over-expressing Ag85B as compared to BCG. Thus, it induces a greater Th1 immune response towards Mtb. Another recombinant BCG vaccine is VPM 1002. It uses protein, listeriolysin that is derived from Listeria monocytogenes to escape from phagolysosomes to the cytosol of the host. Listeriolysin can only work at acidic pH 5.5. But, listeriolysin cannot carry out its activity in the presence of BCG because BCG neutralises the phagosomal pH. Thus, the modification was done by deleting the urease C (ureC) gene in BCG by virtue of which microbial antigens are released into cytosol with better CD8+ T-cells stimulation (Hesseling, et al., 2007). Phase 2 trials were completed comparing rBCG with BCG in newborn babies (Da Costa, et al., 2015).
Subunit and live vector-based vaccines
Subunit vaccines are dead or non-replicating vaccines that can be delivered safely into the human body. Most of the subunit vaccines are based on recombinant fusion proteins with attenuated viral vectors and are used as a BCG booster (Ottenhoff and Kaufmann. 2012). M72/MTB72F is the recombinant fusion protein consisting of Mtb32 and Mtb39 antigens. This vaccine was mixed with either liposomal formulation (AS01) or proprietary oil-in-water emulsion (AS02) with monophosphoryl lipid A and Quillaja saponaria fraction 21 (QS21) (Kaufmann. 2010; McShane, 2011). Based on clinical trials studies, M72 demonstrated high levels of CD4 T-cells in individuals with primed-BCG (Beresdord and Sadoff. 2011). Another recombinant fusion protein is Hybrid I (HI) which consists of early secreted antigenic target 6 (ESAT-6) and Ag85B. HI is combined with adjuvant IC31 that consists of oligodeoxynucleotides and polycationic aminoacids (Kaufmann. 2010). Based on preclinical data, this vaccine increases Th-1 responses against Mtb in mice and guinea pigs (McShane, 2011; Cayabyab, et al., 2012). The viral vector is also used to develop new TB vaccine, for example, the modified vaccinia virus Ankara 85A (MVA85A) which utilizes poxvirus to express Ag85A while Aeras 402 uses a recombinant adenovirus-35 to express Ag85A, 85B and TB10.4 (Charles, et al., 2013). Both of these vaccines are to act as a booster for BCG. MVA85A, shows strong T-helper cells responses by boosting specific CD4+ and CD8+ in the experiment with mice. Evidence also shows that MVA85A is safe and immunogenic in HIV and infected adults in the TB-endemic region (Scriba, et al., 2012).
Killed whole/fragmented cell vaccines
The vaccines are developed for treatment of patients who are already infected with Mtb. The therapeutic vaccines is not only to destroy pathogen in active disease but also in LTBI. However, extra cautions are needed in developing a therapeutic vaccine because the high dosage of Mtb antigens is likely to cause potential risk such as tuberculin shock (Svenson, et al., 2010). This phenomenon was described by Robert Koch and known as Koch’s phenomenon (Kaufmann. 2010). Two heat-inactivated strains (M. vaccae and M. indicus pranii) was tested with a combination of chemotherapy for Mtb infection. RUTI® or therapeutic vaccine is a heat-inactivated Mtb cellular bacterial fragment. It is grown under stress condition and is fragmented and detoxified by Triton X-11. This vaccine is designed to shorten the chemotherapy of LTBI and direct observed treatment short-course (DOTS) (Svenson, et al., 2010).
Multistage, multi-antigenic subunit vaccine
The multi-antigenic, multistage subunit vaccine can be a very useful tool against complex microbes invading host cell by various pathways (Niu, et al., 2011). For Mtb, AID4 polyprotein, multistage subunit vaccine has been developed as a novel vaccine. AID4 emulsified in adjuvant monophosphoryl lipid A (MTO) with BCG showed promising initial results (Wang, et al., 2015). Mtb10.4-HspX (MH) as multistage subunit fusion vaccine as a potential candidate for clinical use (Niu, et al., 2011). Table provides the summary of important TB vaccines that are undergoing human clinical trials.
Table 5: Tuberculosis vaccines in human clinical trials (Sumera et al., 2016)
Types of VaccineNameDescriptionClinical Trial Phase
Recombinant BCGrBCG30Over expressing antigen 85B (Ag85B)Phase-I completed
Viral VectorVPM 1002Used listeriolysin produced by Listeria monocytogenes to support an acidic phagosomal for listeriolysin activity. Allowing BCG antigens to access to MHC I.Phase IIa ongoing
Aeras 422Over expression of Ag85A and Ag85BPhase I
MVA85AAct as a BCG booster by expressing CD4 T cell responses.Phase IIb ongoing
Aeras 402Uses a replication-deficient adenovirus serotype 35 expressing antigens 85A, 85B and TB10.Phase IIb
Recombinant fusion proteinM72/MTB72FRecombinant fusion of Mtb39 and M.tb32 in AS01Phase II
Bacterial fragments
Heat-inactivated Mycobacterium (Inactivated whole/ fragmented mycobacteria)Hybrid 1 (H1)Ag85B-ESAT-6 fused with strong Th1 adjuvant, IC31 Have prolonged Th-1 immunity.Phase I
RUTI®Detoxification, fragmentation of Mtb.Phase II
Mycobacterium vaccae (MOD-901)Multiple-dose of vaccine shown to be safe and give protection in Tb-HIV infected adults who have been given BCG injection during childhood.Phase III
M. indicus pranii (MIP)Applied with chemotherapy for Mtb infection and results shown that it decreases response of inflammatory system.Phase III
Ethical issues
All new TB vaccines are currently passing through different stages of clinical trials. The Clinical trials of new TB vaccines are mostly carried out in TB endemic areas. The populations in these areas are mostly poverty-stricken and poorly educated. They often have limited knowledge about the research and not familiar with human rights (Kaufmann. 2010). The concept of informed written consent becomes an ethical concern as the study population mostly does not fully understand the content of research protocol. In order to address this issue of grave concern, the WHO is now trying to introduce regulatory challenges for testing new TB vaccines in these under-developed and developing countries.
Common anti-tb drug metabolisms & toxicities
Drug related toxicity is an unlucky result of this TB treatment due to the various antibiotics used and the comparatively long duration of treatment. Rarely, the severity of adverse effects practiced by the patient forces the discontinuation of the antibiotic program. This in turn makes possible the emergence of DR-TB. Most anti-TB drugs cause hepatotoxicity, and other side effects such as neurological syndrome, rash and visual disturbances (mainly with ethambutol) (Sarkar et al., 2016).
Newer antituberculosis drug delivery systems
During the last decade, newer drug delivery systems, such as liposomes, polymeric micro/nanoparticles and solid lipid nanoparticles have been developed. These newer drug delivery systems can be administered through oral, subcutaneous, intravenous or inhaled route. The newer drug delivery systems have the potential advantages of improving patient adherence, reduce pill burden and shorten the treatment duration. The term “nanoparticle” refers to a colloidal particle with a size of less than 1 micron. Nanoparticles can be made from a wide array of biocompatible materials, like natural substances (e.g. alginate and albumin) or synthetic substances (e.g. polylactides, solid lipids) (Shegokar et al., 2011; Smith. 2011; Sosnik et al., 2010).
Application of nanotechnologies for treatment of tuberculosis
Translational research has paved the way for the development of innovative nanotechnology-based drug delivery systems. Applications of nanotechnologies for the treatment of TB (Table 6).
Table 6: Nanotechnologies applied to the treatment of tuberculosis
S. No.Nanotechnologies
1.Nanodispersions•Nanosuspensions
•Nanoemulsions
•Niosomes
2.Polymeric and nonpolymeric nanoparticles
3.Polymeric micelles and other self-assembled structures
Nanodispersions
Nanosuspensions are submicron colloidal dispersions of pure drugs stabilized with surfactants. Nanonization (reduction of the average size of solid drug particles to the nanoscale by top milling or grind¬ing) facilitates improved solubility of drugs that are both with poor water and lipid solubility. Nanoemulsions are thermodynamically stable oil-in-water dispersions. Their drop size is between 10 mm and 100 nm and has the advantages of being generated spontane¬ously and ease of production in a large scale and being sterilized by filtration. Niosomes are thermodynamically stable liposome-like vesicles produced with the hydration of cholesterol, charge-inducing components like charged phospholipids and non-ionic surfactants. They can host hydrophilic drugs within the core and lipophilic ones by entrapment in hydrophobic domains.
Polymeric and nonpolymeric nanoparticles
Polymeric and nonpolymeric nanoparticles have been explored as means for drug solubilization, stabilization and targeting, and facilitate two kinds of systems, namely nanocapsules and nanospheres.
Polymeric micelles
Polymeric micelles are nanocarriers generated by the self-assembly of amphiphilic polymers in water above the critical micellar concen¬tration. Dendrimers are macromolecules displaying well defined, regularly hyperbranched and three-dimensional architecture that facilitate drug encapsulation. Liposomes are nano- to microsized vesicles comprising a phospholipid bilayer that surrounds an aque¬ous core. The hydrophobic domain can be utilized to entrap insolu¬ble agents and the core enables the encapsulation of water soluble drugs (Pinheiro et al., 2011).
Nanoparticles can be formulated as monolithic nanoparticles (nanospheres) that embed the drug in the polymeric matrix or nanocapsules where the drug is confined within a hydrophobic or hydrophilic core surrounded by a definitive “capsule”. Entrapment of anti-TB drugs in the poly DL-lactide-coglycolide (PLG) microspheres has been extensively studied. Oral delivery of nanoparticle-encapsulated anti-TB drugs has been shown to have several advantages over the currently used oral drugs in terms of increasing the efficacy of the used drugs, reducing degradation in the bowels, and increasing uptake and bioavailability. Nanoparticle technology also allows intravenous use of first line anti-TB drugs as well as inhalable drugs. The efficacy of O-stearyl amylopectin (O-SAP)-coated liposomal anti-TB drugs given by intravenous route appears promising (Shegokar et al., 2011; Smith. 2011; Sosnik et al., 2010). Inhaled nanoparticle-based administration of anti-TB drugs has the advantages of direct delivery of the drugs to the site of infection, and bypassing the first-pass metabolism (Misra et al., 2011). Nanoparticle delivery of anti-TB drugs also provides sustained release in both blood plasma as well as organ tissues. Additionally, as nanoparticles are preferentially engulfed by the alveolar macrophage, releasing the anti-TB drugs directly into the macrophage and this targeted drug delivery holds significant potential in combating the TB bacillus. Human clinical trials are awaited in near future to evaluate these innovative novel modalities of drug delivery and their impact on TB control.
Future prospects
With X/MDR-TB emerging as a global threat to TB control, eradication of TB requires not only new drugs and treatment regimens, but newer drug delivery systems. The repurposed and emerging newer anti-TB drugs must be carefully evaluated in well designed controlled clinical trials so as to generate quality evidence regarding their efficacy. The quest for newer and more efficient anti-TB drugs must be pursued relentlessly. More than 12 vaccines are currently undergoing clinical trials in various parts of the world. However, we are not sure whether these vaccines can fully prevent TB in the population. This is because there are gaps in scientific knowledge in TB and its vaccine development. A research into lung immunity may provide some information whether the regulatory T cells play an important role in modifying the susceptibility of Mtb (Schwander and Dheda. 2011). The advanced technologies and development in Bioinformatics have increased the possibility of finding novel candidate antigens based on the genomic sequence (Cayabyab, et al., 2012). A biomarker is one of a valuable tool in developing TB vaccine. The clinical endpoints can be determined with the help of biomarker. This could also reduce the cost and at the same time accelerate the clinical trials by providing useful information. The TB biomarker also can be used in the early diagnosis of active TB and the prediction of reactivation risk, latent infection as well as treatment outcome (Kaufmann. 2010; Lawn and Zumla, 2011).
Discussion
Despite current anti-TB chemotherapy, TB remains one of the most important infectious diseases worldwide. The main complications to control the disease are the HIV epidemic that has radically increased risk for developing TB, the growing emergence of MDR-TB, XDR-TB and the uprising of continual infections to treatment with conventional anti-TB drugs (Corbett, et al., 2003; Gomez, and McKinney. 2004; Smith, et al., 2003; CDC. 2006; Zhang. 2005). According to their mechanism of action, first and second line anti-TB drugs can be groups as cell wall inhibitors (INH, EBMl, ethionammide, cycloserine), nucleic acid synthesis inhibitors (RIF, quinolones), inhibitors of membrane energy metabolism (PZA) and protein synthesis inhibitors (SM, kanamycin). The existing TB drugs are consequently only able to target actively growing bacteria through the inhibition of cell developments such as cell wall biogenesis and DNA replication. This involved that current TB chemotherapy is characterized by a well-organized bactericidal activity but tremendously weak sterilizing activity, defined as the capability to kill the slowly growing or metabolizing bacteria that persist after the growing INH and in addition to a FQ drug and an injectable drug (kanamycin, amikacin or capreomycin) among the second-line drugs. The XDR-TB creates this form of TB particularly awkward to treat with available drugs. The current condition clearly displayed the required for a re-evaluation of approach to treating TB (Garay. 2004; Management of MDR-TB. 2009; Mayekar, et al., 2010). Various anti-TB molecules with different pharmacophores apart from currently used drugs with potential anti-TB activity with the specific purposes to identify promising candidates for improvement of drugs for TB in recent year. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Some compounds are currently in clinical development, while others are being examined pre-clinically in an effort to discover new drug molecules for the target based TB treatment (Kamal et al., 2007). The specific aim of bringing new, inexpensive TB drugs that would decrease treatment period and affective against latent infections and/or MDR-TB/XDR-TB, cheap and effortlessly available.
Even after so many decades, TB remains one of the major causes of mortality and morbidity. This is due to the absence of any safe, stable and inexpensive vaccine providing life-long immunity. The scientists are still trying to solve the mystery of how the Mtb evades and escapes from the host adaptive immune responses. The only vaccine for TB which is BCG that has been existing for almost 100 years is losing its potency. Based on the evidence reviewed in this article, most of the new TB vaccine candidates have shown good efficacy and safety in trials on animals. Search for new TB vaccines will continue, even though, there is still no potent vaccine successfully passing through all stages of clinical and field trials. This is because the vaccines in clinical trials will prevent and reduce the number of TB cases around the world, but not completely destroy the pathogen. Thus, the next generation of vaccines that can fully eradicate Mtb would always be required.
Conclusion
Tuberculosis (TB) infection occurs via aerosol, and inhalation of a few droplets containing Mtb bacilli. Most cases of TB are pulmonary and acquired by person to person transmission of air-borne droplets of organisms. It can be diagnosed by PPD, IGRA, Sputum studies, X-rays and Biopsies. TB is a leading cause of death since time immemorial and it continues to cause immense human misery even today. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) has been threatening to destabilize TB control globally. TB has remained a neglected disease and since the introduction of rifampicin, anti-TB drug discovery has been sluggish. Since then, no new drug has become available that can be compared to rifampicin in terms of utility and safety. There is an urgent need for new anti-TB drugs that are more effective and have less toxicity. There is also a need for newer and innovative anti-TB drug delivery systems. Newer fluoroquinolones, especially moxifloxacin has been shown to improve the activity of standard anti-TB treatment regimen when substituted for ethambutol and is studied to shorten the treatment duration in drug-susceptible TB. Rifapentine is a rifamycin that is being extensively re-evaluated. While its potential sterilizing activity has been documented in mice, the same was not evident in a recent short-term clinical trial. Clofazimine, a fat-soluble dye with experimental activity against TB, is being evaluated for the treatment of MDR-TB. The phenothiazine neuroleptic thioridazine has been found to be useful for XDR-TB. Among newer drugs, the nitro-dihydro-imidazooxazole derivative delamanid (OPC67683), the diarylquinoline bedaquiline (TMC207), the nitroimidazole-oxazine (PA-824) appear most promising. The newer oxazolidinones PNU-100480 and AZD-5847 have been shown to be as active as linezolid and are less toxic. The ethambutol analogue SQ109 does not have cross-resistance with ethambutol and appears to have the potential for a synergistic activity in combined regimens. Eradication of TB requires not only new drugs and treatment regimens, but newer drug delivery systems, especially those based on nanotechnologies. These newer drug-delivery systems can be administered through oral, subcutaneous, intravenous or inhaled route. The newer drug delivery systems, especially nanotechnology-based drug delivery systems have the potential advantages of improving patient adherence, reduce pill burden and shorten the treatment duration. Human clinical trials are awaited in near future to evaluate these innovative novel modalities of drug delivery and their impact on TB control.
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