|Year : 2018 | Volume
| Issue : 1 | Page : 16-19
Anti-tuberculosis therapy: Urgency for new drugs and integrative approach
Lingaraja Jena1, Bhaskar C Harinath2
1 Bioinformatics Centre, Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra, India
2 JB Tropical Disease Research Centre, Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra, India
|Date of Web Publication||5-Mar-2018|
Dr. Bhaskar C Harinath
JB Tropical Disease Research Centre, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha - 442 102, Maharashtra
Source of Support: None, Conflict of Interest: None
Tuberculosis (TB) remains the major health problem causing morbidity and mortality throughout the world. Increase in multidrug resistant, extensively drug-resistant, and totally drug-resistant cases of tuberculosis are causing concern to the health administrators of TB control programs. In spite of tremendous research on drug targets and drugs in TB, no new drug which is safer and more effective, has come out. This mini-review focuses on different important drug targets in Mycobacterium tuberculosis reported and emphasizes the urgency for new drug development and integrative approach for successful control of TB.
Keywords: Drug resistant, drug targets, integrative therapy, tuberculosis
|How to cite this article:|
Jena L, Harinath BC. Anti-tuberculosis therapy: Urgency for new drugs and integrative approach. Biomed Biotechnol Res J 2018;2:16-9
|How to cite this URL:|
Jena L, Harinath BC. Anti-tuberculosis therapy: Urgency for new drugs and integrative approach. Biomed Biotechnol Res J [serial online] 2018 [cited 2020 Apr 8];2:16-9. Available from: http://www.bmbtrj.org/text.asp?2018/2/1/16/226575
| Introduction|| |
Tuberculosis (TB) remains a major health problem and the leading cause of morbidity and mortality throughout the world. Around 10.4 million new patients and 1.4 million deaths in 2015 among which 95% deaths were reported to be in developing countries. TB caused by drug-resistant Mycobacterium tuberculosis (MTB) raises the multidrug-resistant (MDR) cases of TB and as a result, the standard treatment-directly observed therapy, short course, is failing in many settings. A recommended 4 regimen (Isoniazid [INH], ethambutol [EMB], Rifampicin [RIF], and Pyrazinamide [PZA]) followed for 7 decennia have not been effective in control of TB transmission. Further, the recent increase in cases of HIV and TB co-infection has caused a more serious problem with drug resistant, MDR, extensively drug resistant (XDR), and totally drug-resistant (TDR) cases of TB. Most MDR and XDR clinical strains of MTB are found to be resistant to all anti-tubercular drugs. No drug is safe when used for a long time. For example, 82 different enzymes of mycobacteria associated with the interaction of INH, resulting in mutation, and INH drug resistance. Velayati et al.(2016) reported considerable thickening of cell wall in resistant TB organism., To strengthen, TB control program the health ministry in India changed the treatment strategy for TB from thrice a week (short course intermittent chemotherapy) to daily drug regimen using fixed-dose combination tablets made available free of cost at pharmacies to dispense to TB patients. While we are taking small steps, the MTB organism is taking giant steps transforming to MDR, XDR and TDR. In the light of lack of success in TB control and increased drug-resistant cases, there is urgent need for reevaluation of chemotherapy alone program and take steps to integrative therapy approach including segregation, nutrition supplement, and administration of immunomodulator herbal drugs (Rasayana) for drug-resistant cases (MDR, etc.,) to stop transmission of resistant strains in the community.
| MTB Drug Targets|| |
Despite significant research in TB across the globe, no new drug has emerged. Out of various drug targets identified in MTB, few well-known drug targets are InhA, RpoB, FabC, FabD, KasA, Ndh, Glf, EfpA, EmbB, ES-31, Cyp125, IniA, etc., need extensive study in task force approach to develop new drugs for TB. FASII enoyl-ACP reductase (InhA) is the only well-validated target of the TB drug INH and has been a target of rational drug design., It plays an important role in the synthesis of mycolic acid, a major lipid of the mycobacterial cell wall. Ollinger et al.(2012) proposed ClpP protease in MTB as an important drug target. Normally, the Clp system has a major role in basic metabolism, stress responses, and pathogenic mechanisms. There are two ClpP proteolytic subunits, present in MTB, i.e., ClpP1 is essential for viability in this organism and in contrast the overexpression of ClpP2 was reported to be toxic. Further, the MenA (1,4-dihydroxy-2-naphthoate octaprenyltransferase) encoded by Rv0534c in MTB has been reported as potential drug target in MTB. Kurosu and Crick, observed the effective killing of nonreplicating MTB using MenA inhibitors and also reported the potential anti-TB effect of these inhibitors against different drug-resistant Mycobacterium spp. Further, sulfur metabolic pathways are reported to be essential for survival and the expression of virulence in many pathogenic bacteria, including MTB. As microbial sulfur metabolic pathways are largely absent in humans, and therefore, represent unique targets for therapeutic intervention., The MTB genome encodes 11 serine/threonine protein kinases (STPKs). The MTB phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of MTB biology, supporting a critical role for the STPKs in regulating the MTB physiology. Thus, these STPKs are reported as suitable drug targets for MTB. Three mycobacteria-specific proteins in MTB such as Rv0203, MmpL3, and MmpL11 proposed to play an important role in mediating MTB heme iron uptake and thus reported as excellent drug targets.
In our laboratory, we have isolated an Excretory-secretory antigen (ES-31) of molecular weight of 31 kDa. After its characterization, it is found that it has serine protease as well as lipase activities and shown to be a chymotrypsin-like protein which is having catalytic triad responsible for both activities. Further, addition of serine protease inhibitors (53%–76%), metalloprotease inhibitor (46%–61%), lipase inhibitor (61%), or anti-ES-31 serine protease antibody (89%) strongly inhibited the MTB H37Ra growth in axenic culture. The importance of ES-31 antigen for the survival of MTB H37Ra and H37Rv bacilli has been shown by 77% and 78% growth inhibition in macrophage culture by protease inhibitor Pefabloc. Inhibition of ES-31 leads to growth inhibition of MTB bacilli, suggesting that it may be an important drug target for exploring new drugs for TB. Iron acquisition and storage within MTB is very crucial for the growth and virulence of MTB. MTB has one MbtE protein for iron acquisition and two storage proteins, bacterioferritin (BfrA) and a ferritin-like protein (BfrB), which have been reported to be essential for MTB protection against oxidative stress, growth in macrophages, and virulence in guinea pigs. The mbtE deletion mutants are unable to synthesize mycobactins and are attenuated for growth in vitro, macrophages, and guinea pigs, highlighting the importance of mycobactin biosynthesis for the growth and virulence of Mtb and establishing this pathway as a potential target for the TB drug development.
The MTB genome contains 13 genes that encode 12 resistance, nodulation, and cell division (RND) proteins designated mycobacterial membrane protein large (MmpL). RND proteins transport a variety of cationic, anionic, or neutral compounds, including various drugs, heavy metals, aliphatic and aromatic solvents, bile salts, fatty acids, detergents, and dyes, across the cytoplasmic membrane., Thus, MmpL protein of MTB has been identified as an important drug target. MTB adapts its metabolism to the environmental conditions to which it is exposed. Several metabolic enzymes have been validated as drug targets; the multifunctionality of some of these enzymes makes them of particular interest. The enzymes of the glyoxylate shunt, isocitrate lyase, and malate synthase (GlcB), have long been and remain of interest to TB drug discovery.
In Mtb, cholesterol is degraded by a specialized pathway, i.e., cholesterol degradation pathway and steroid C26-monooxygenase, an important enzyme of this pathway is reported to be a good drug target.,, Wankhade et al.(2017) applied in silico screening technique and identified 15 natural compounds against C26-monooxygenase (CYP125) enzyme of MTB and observed the inhibitory effect of Sesamin, and β-sitosterol on MTB growth in culture study.
The MTB UDP-galactopyranose mutase is an essential flavoenzyme for mycobacterial viability and an important component of cell wall. It catalyzes the inter-conversion of UDP-galactopyranose into UDP-galactofuranose, a key building block for cell wall construction, essential for linking the peptidoglycan and mycolic acid cell wall layers in MTB through a 2-keto intermediate. Further, as this enzyme is not present in humans, it is an excellent therapeutic target for MTB. Aspartate-β-semialdehyde dehydrogenase of MTB also reported as a potential therapeutic target of MTB.
Further, Vashisht et al. (2012) employed interactome pathway with STRING-based network techniques to identify MTB drug targets. Anishetty et al.(2005) identified 67 new targets of MTB through metabolic pathway analysis. In addition to identifying novel drug targets, different studies also reported different potential inhibitors for MTB through in silico as well asin vitro approaches.,,,,,,,,,
| Conclusion|| |
In spite of vast research on drug targets and drugs in TB, this illness, still, today, remains to be one of the leading causes of morbidity and mortality throughout the world. Although there are many drug targets reported in TB.,, and many inhibitors proposed for those targets, still we are struggling to find a more effective drug for TB with less toxicity. There is an urgent need for a focused study on the reported drug targets to screen synthetic, phytochemicals, and herbal compounds in a task force approach on war footing to find new anti-TB drugs before drug-resistant TB overtakes control programs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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