|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 2019 Mar 23];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.
| References|| |
Forrellad MA, Klepp LI, Gioffré A, Sabio y García J, Morbidoni HR, de la Paz Santangelo M, et al.
Virulence factors of the Mycobacterium tuberculosis
complex. Virulence 2013;4:3-66.
World Health Organization. WHO Global Tuberculosis Report 2017. World Health Organization; 2017.
Trauner A, Borrell S, Reither K, Gagneux S. Evolution of drug resistance in tuberculosis: Recent progress and implications for diagnosis and therapy. Drugs 2014;74:1063-72.
Jena L, Nayak T, Deshmukh S, Wankhade G, Waghmare P, Harinath BC. Isoniazid with multiple mode of action on various mycobacterial enzymes resulting in drug resistance. J Infect Dis Ther 2016;4:297.
Velayati AA, Farnia P, Farahbod AM. Overview of drug-resistant tuberculosis worldwide. Int J Mycobacteriol 2016;5 Suppl 1:S161.
Mdluli K, Kaneko T, Upton A. Tuberculosis drug discovery and emerging targets. Ann N
Y Acad Sci 2014;1323:56-75.
Marrakchi H, Lanéelle G, Quémard A. InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 2000;146(Pt 2):289-96.
Pan P, Tonge PJ. Targeting inhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds. Curr Top Med Chem 2012;12:672-93.
Ollinger J, O'Malley T, Kesicki EA, Odingo J, Parish T. Validation of the essential ClpP protease in Mycobacterium tuberculosis
as a novel drug target. J Bacteriol 2012;194:663-8.
Kurosu M, Crick DC. MenA is a promising drug target for developing novel lead molecules to combat Mycobacterium tuberculosis
. Med Chem 2009;5:197-207.
Bhave DP, Muse WB 3rd
, Carroll KS. Drug targets in mycobacterial sulfur metabolism. Infect Disord Drug Targets 2007;7:140-58.
Paritala H, Carroll KS. New targets and inhibitors of mycobacterial sulfur metabolism. Infect Disord Drug Targets 2013;13:85-115.
Prisic S, Husson RN. Mycobacterium tuberculosis
serine/Threonine protein kinases. Microbiol Spectr 2014;2:10.
Owens CP, Chim N, Goulding CW. Insights on how the Mycobacterium tuberculosis
heme uptake pathway can be used as a drug target. Future Med Chem 2013;5:1391-403.
Wankhade G, Majumdar A, Kamble P, Harinath BC. Mycobacterial secretory SEVA TB ES-31 antigen, a chymotrypsin-like serine protease with lipase activity and drug target potential. Biomed Res 2011;22:45-8.
Gupta V, Gupta RK, Khare G, Salunke DM, Tyagi AK. Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of bacterioferritin A from Mycobacterium tuberculosis
. Acta Crystallogr Sect F
Struct Biol Cryst Commun 2008;64:398-401.
McMath LM, Habel JE, Sankaran B, Yu M, Hung LW, Goulding CW, et al.
Crystallization and preliminary X-ray crystallographic analysis of a Mycobacterium tuberculosis
ferritin homolog, bfrB. Acta Crystallogr Sect F
Struct Biol Cryst Commun 2010;66:1657-61.
Reddy PV, Puri RV, Khera A, Tyagi AK. Iron storage proteins are essential for the survival and pathogenesis of Mycobacterium tuberculosis
in THP-1 macrophages and the guinea pig model of infection. J Bacteriol 2012;194:567-75.
Reddy PV, Puri RV, Chauhan P, Kar R, Rohilla A, Khera A, et al.
Disruption of mycobactin biosynthesis leads to attenuation of Mycobacterium tuberculosis
for growth and virulence. J Infect Dis 2013;208:1255-65.
Paulsen IT, Brown MH, Skurray RA. Proton-dependent multidrug efflux systems. Microbiol Rev 1996;60:575-608.
Putman M, van Veen HW, Konings WN. Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev 2000;64:672-93.
Rhee KY, de Carvalho LP, Bryk R, Ehrt S, Marrero J, Park SW, et al.
Central carbon metabolism in Mycobacterium tuberculosis
: An unexpected frontier. Trends Microbiol 2011;19:307-14.
Höner Zu Bentrup K, Miczak A, Swenson DL, Russell DG. Characterization of activity and expression of isocitrate lyase in Mycobacterium avium
and Mycobacterium tuberculosis
. J Bacteriol 1999;181:7161-7.
Smith CV, Huang CC, Miczak A, Russell DG, Sacchettini JC, Höner zu Bentrup K, et al.
Biochemical and structural studies of malate synthase from Mycobacterium tuberculosis
. J Biol Chem 2003;278:1735-43.
Ouellet H, Johnston JB, de Montellano PR. Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis
. Trends Microbiol 2011;19:530-9.
McLean KJ, Lafite P, Levy C, Cheesman MR, Mast N, Pikuleva IA, et al.
The structure of Mycobacterium tuberculosis
CYP125: Molecular basis for cholesterol binding in a P450 needed for host infection. J Biol Chem 2009;284:35524-33.
Hudson SA, McLean KJ, Munro AW, Abell C. Mycobacterium tuberculosis
cytochrome P450 enzymes: A cohort of novel TB drug targets. Biochem Soc Trans 2012;40:573-9.
Wankhade G, Kamble S, Deshmukh S, Jena L, Waghmare P, Harinath BC. Inhibition of mycobacterial CYP125 enzyme by sesamin and β-sitosterol: An in silico
study. Biomed Biotechnol Res J 2017;1:49-54. [Full text]
Dykhuizen EC, May JF, Tongpenyai A, Kiessling LL. Inhibitors of UDP-galactopyranose mutase thwart mycobacterial growth. J Am Chem Soc 2008;130:6706-7.
Khan S, Somvanshi P, Bhardwaj T, Mandal RK, Dar SA, Wahid M, et al.
Aspartate-β-semialdeyhyde dehydrogenase as a potential therapeutic target of Mycobacterium tuberculosis
H37Rv: Evidence from in silico
elementary mode analysis of biological network model. J Cell Biochem 2017; doi: 10.1002/jcb.26458. [Epub ahead of print].
Vashisht R, Mondal AK, Jain A, Shah A, Vishnoi P, Priyadarshini P, et al.
Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis
. PLoS One 2012;7:e39808.
Anishetty S, Pulimi M, Pennathur G. Potential drug targets in Mycobacterium tuberculosis
through metabolic pathway analysis. Comput Biol Chem 2005;29:368-78.
Jee B, Kumar S, Yadav R, Singh Y, Kumar A, Sharma N, et al.
Ursolic acid and carvacrol may be potential inhibitors of dormancy protein small heat shock protein16.3 of Mycobacterium tuberculosis
. J Biomol Struct Dyn 2017. [Epub ahead of print].
Santa Maria JP Jr., Park Y, Yang L, Murgolo N, Altman MD, Zuck P, et al.
Linking high-throughput screens to identify moAs and novel inhibitors of Mycobacterium tuberculosis
dihydrofolate reductase. ACS Chem Biol 2017;12:2448-56.
Lone MY, Athar M, Gupta VK, Jha PC. Prioritization of natural compounds against Mycobacterium tuberculosis
3-dehydroquinate dehydratase: A combined in silico
study. Biochem Biophys Res Commun 2017;491:1105-11.
Lone MY, Athar M, Gupta VK, Jha PC. Identification of Mycobacterium tuberculosis
enoyl-acyl carrier protein reductase inhibitors: A combined in silico
analysis. J Mol Graph Model 2017;76:172-80.
Pandey P, Lynn AM, Bandyopadhyay P. Identification of inhibitors against α-isopropylmalate synthase of Mycobacterium tuberculosis
using docking-MM/PBSA hybrid approach. Bioinformation 2017;13:144-8.
Martinelli LKB, Rotta M, Villela AD, Rodrigues-Junior VS, Abbadi BL, Trindade RV, et al.
Functional, thermodynamics, structural and biological studies of in silico
-identified inhibitors of Mycobacterium tuberculosis
enoyl-ACP(CoA) reductase enzyme. Sci Rep 2017;7:46696.
Inturi B, Pujar GV, Purohit MN. Recent advances and structural features of enoyl-ACP reductase inhibitors of Mycobacterium tuberculosis
. Arch Pharm (Weinheim) 2016;349:817-26.
Islam MA, Pillay TS. Identification of promising DNA gyrB inhibitors for tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies. Chem Biol Drug Des 2017;90:282-96.
Saharan VD, Mahajan SS. Development of gallic acid formazans as novel enoyl acyl carrier protein reductase inhibitors for the treatment of tuberculosis. Bioorg Med Chem Lett 2017;27:808-15.
Billones JB, Carrillo MC, Organo VG, Sy JB, Clavio NA, Macalino SJ, et al. In silico
discovery andin vitro
activity of inhibitors against Mycobacterium tuberculosis
7,8-diaminopelargonic acid synthase (Mtb bioA). Drug Des Devel Ther 2017;11:563-74.
Chiarelli LR, Mori G, Esposito M, Orena BS, Pasca MR. New and old hot drug targets in tuberculosis. Curr Med Chem 2016;23:3813-46.
Chopra P, Meena LS, Singh Y. New drug targets for Mycobacterium tuberculosis
. Indian J Med Res 2003;117:1-9.