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Current Drug Therapy

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ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

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Review Article

Drug Targets, Current and Future Therapeutics for the Treatment of Multi Drug Resistant Tuberculosis with their Clinical Applications: A Critical Review

Author(s): Deepshikha Singh, Vikram Singh, Subhankar P. Mandal, Karen Dsouza, B.R. Prashantha Kumar and Sheshagiri R. Dixit*

Volume 19, Issue 3, 2024

Published on: 20 September, 2023

Page: [317 - 326] Pages: 10

DOI: 10.2174/1574885519666230830125139

Price: $65

Abstract

Multi drug-resistant or extensive drug resistance Mycobacterium tuberculosis poses numerous challenges for health care workers and for public health authorities. Treating multidrug resistant or extensive drug resistance tuberculosis continues to be a difficult task, as a longer regimen is associated with a higher number of adverse drug events and economic burden and has a significant negative effect on health care resources. Many trials and observational studies were conducted. Few studies are underway to develop the universal regimen and improve the outcomes related to multi or extensive drug resistance tuberculosis with a shorter regimen duration. The current review will discuss which drug inhibits what target, their synthesis, genetic aspects, repurposed drugs, novel drugs, and extensive trials for the treatment of multi or extensive drug resistance tuberculosis.

Keywords: Multi drug resistance, extensive drug resistance, repurposed drug, novel drugs, anti-TB clinical trials, anti-TB drug pipeline.

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[1]
Holmes KK, Bertozzi S, Bloom BR, Eds. The International bank for reconstruction and development. 2017. Available from: https://www.worldbank.org/en/who-we-are/ibrd
[2]
World Health Organization. Tuberculosis Report. 2020. XLIX
[3]
WHO releases new global lists of high-burden countries for TB, HIV-associated TB and drug-resistant TB.2021. Available from: https://www.who.int/news/item/17-06-2021-who-releases-new-global-lists-of-high-burden-countries-for-tb-hiv-associated-tb-and-drug-resistant-tb
[4]
More UA, Joshi SD, Aminabhavi TM, Kulkarni VH, Badiger AM, Lherbet C. Discovery of target based novel pyrrolyl phenoxy derivatives as antimycobacterial agents: An in silico approach. Eur J Med Chem 2015; 94: 317-39.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.013] [PMID: 25771110]
[5]
Vilchèze C. Mycobacterial cell wall: A source of successful targets for old and new drugs. Appl Sci 2020; 10(7): 2278.
[http://dx.doi.org/10.3390/app10072278]
[6]
WHO best-practice statement on the off-label use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis. 2017. Available from: https://apps.who.int/iris/handle/10665/258941
[7]
Almeida L. De. Final treatment outcomes of multidrug- and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens. Eur Respir J 2017; 50(5): 1701105.
[http://dx.doi.org/10.1183/13993003.01105-2017] [PMID: 29122917]
[8]
Pranger AD, van der Werf TS, Kosterink JGW, Alffenaar JWC. The role of fluoroquinolones in the treatment of tuberculosis in 2019. Drugs 2019; 79(2): 161-71.
[http://dx.doi.org/10.1007/s40265-018-1043-y] [PMID: 30617959]
[9]
Chan PF, Germe T, Bax BD, et al. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc Natl Acad Sci 2017; 114(22): E4492-500.
[http://dx.doi.org/10.1073/pnas.1700721114] [PMID: 28507124]
[10]
Brown-Elliott BA, Rubio A, Wallace RJ Jr. In vitro susceptibility testing of a novel benzimidazole, SPR719, against nontuberculous mycobacteria. Antimicrob Agents Chemother 2018; 62(11): e01503-18.
[http://dx.doi.org/10.1128/AAC.01503-18] [PMID: 30126964]
[11]
Locher CP, Jones SM, Hanzelka BL, et al. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. Antimicrob Agents Chemother 2015; 59(3): 1455-65.
[http://dx.doi.org/10.1128/AAC.04347-14] [PMID: 25534737]
[12]
Talley AK, Thurston A, Moore G, et al. First-in-human evaluation of the safety, tolerability, and pharmacokinetics of SPR720, a novel oral bacterial DNA gyrase (GyrB) inhibitor for mycobacterial infections. Antimicrob Agents Chemother 2021; 65(11): e01208-21.
[http://dx.doi.org/10.1128/AAC.01208-21] [PMID: 34491803]
[13]
Makadia JS, Jain A, Patra SK, Sherwal BL, Khanna A. Emerging trend of mutation profile of rpoB gene in MDR tuberculosis, North India. Indian J Clin Biochem 2012; 27(4): 370-4.
[http://dx.doi.org/10.1007/s12291-012-0228-5] [PMID: 24082462]
[14]
Lin W, Mandal S, Degen D, et al. Structural basis of mycobacterium tuberculosis transcription and transcription inhibition. Mol Cell 2017; 66(2): 169-179.e8.
[http://dx.doi.org/10.1016/j.molcel.2017.03.001] [PMID: 28392175]
[15]
Maffioli SI, Sosio M, Ebright RH, Donadio S. Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. J Ind Microbiol Biotechnol 2019; 46(3-4): 335-43.
[http://dx.doi.org/10.1007/s10295-018-2109-2] [PMID: 30465105]
[16]
Maffioli SI, Zhang Y, Degen D, et al. Antibacterial nucleoside-analog inhibitor of bacterial rna polymerase. Cell 2017; 169(7): 1240-1248.e23.
[http://dx.doi.org/10.1016/j.cell.2017.05.042] [PMID: 28622509]
[17]
Chellat MF, Riedl R. Pseudouridimycin: The first nucleoside analogue that selectively inhibits bacterial rna polymerase. Angew Chem Int Ed 2017; 56(43): 13184-6.
[http://dx.doi.org/10.1002/anie.201708133] [PMID: 28895263]
[18]
Kwon NH, Fox PL, Kim S. Aminoacyl-tRNA synthetases as therapeutic targets. Nat Rev Drug Discov 2019; 18(8): 629-50.
[http://dx.doi.org/10.1038/s41573-019-0026-3] [PMID: 31073243]
[19]
Li X, Hernandez V, Rock FL, et al. Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[ c][1,2]oxaborol-1(3 H)-ol (GSK656). J Med Chem 2017; 60(19): 8011-26.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00631] [PMID: 28953378]
[20]
Tenero D, Derimanov G, Carlton A, et al. First-time-in-human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment. Antimicrob Agents Chemother 2019; 63(8): e00240-19.
[http://dx.doi.org/10.1128/AAC.00240-19] [PMID: 31182528]
[21]
Joshi S, More U, Sorathiya S, Koli D, Aminabhavi T. Pyrrolyl thiadiazoles as Mycobacterium tuberculosis inhibitors and their in silico analyses. Res Rep Med Chem 2015; 5: 1-20.
[http://dx.doi.org/10.2147/RRMC.S80395]
[22]
Joshi SD, Kumar D, Dixit SR, Joshi AS, Aminabhavi TM. Drug resistance of antitubercular agents at the genetic level in mycobacterium species: A road map to drug development for counteracting the resistance. Mini Rev Org Chem 2016; 13(4): 262-80.
[http://dx.doi.org/10.2174/1570193X13666160613094646]
[23]
Lu Y, Zheng M, Wang B, et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation. Antimicrob Agents Chemother 2011; 55(11): 5185-93.
[http://dx.doi.org/10.1128/AAC.00699-11] [PMID: 21844321]
[24]
Dalcolmo M, Gayoso R, Sotgiu G, et al. Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: A nationwide report from Brazil. Eur Respir J 2017; 49(3): 1602445.
[http://dx.doi.org/10.1183/13993003.02445-2016] [PMID: 28331044]
[25]
Tiberi S, Sotgiu G, D’Ambrosio L, et al. Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. Eur Respir J 2016; 47(6): 1758-66.
[http://dx.doi.org/10.1183/13993003.00214-2016] [PMID: 27076583]
[26]
Tiberi S, Sotgiu G, D’Ambrosio L, et al. Comparison of effectiveness and safety of imipenem/clavulanate added to an optimised background regimen (OBR) versus OBR controls regimens in the treatment of multidrug and extensively drug-resistant tuberculosis. Clin Infect Dis 2016; 62(9): 1189-90.
[http://dx.doi.org/10.1093/cid/ciw088] [PMID: 26908794]
[27]
Diacon AH, van der Merwe L, Barnard M, et al. β-Lactams against Tuberculosis-New trick for an old dog? N Engl J Med 2016; 375(4): 393-4.
[http://dx.doi.org/10.1056/NEJMc1513236] [PMID: 27433841]
[28]
Tiberi S, D’Ambrosio L, De Lorenzo S, et al. Ertapenem in the treatment of multidrug-resistant tuberculosis: First clinical experience. Eur Respir J 2016; 47(1): 333-6.
[http://dx.doi.org/10.1183/13993003.01278-2015] [PMID: 26585427]
[29]
Sotgiu G, Pontali E, Migliori GB. Linezolid to treat MDR-/XDR-tuberculosis: Available evidence and future scenarios. Eur Respir J 2015; 45(1): 25-9.
[http://dx.doi.org/10.1183/09031936.00145014] [PMID: 25552734]
[30]
te Brake LHM, de Knegt GJ, de Steenwinkel JE, et al. The Role of efflux pumps in tuberculosis treatment and their promise as a target in drug development: Unraveling the black box. Annu Rev Pharmacol Toxicol 2018; 58(1): 271-91.
[http://dx.doi.org/10.1146/annurev-pharmtox-010617-052438] [PMID: 28715978]
[31]
Amaral L, Viveiros M. Thioridazine: A non-antibiotic drug highly effective, in combination with first line anti-tuberculosis drugs, against any form of antibiotic resistance of Mycobacterium tuberculosis due to its multi-mechanisms of action. Antibiotics 2017; 6(1): 3.
[http://dx.doi.org/10.3390/antibiotics6010003] [PMID: 28098814]
[32]
DR-TB Scale-Up Call to action to accelarate access to DR-TB drugs: 2016 update. 2016. Available from: https://msfaccess.org/call-action-accelerate-access-dr-tb-drugs
[33]
Guglielmetti L, Jaspard M, Le Dû D, et al. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J 2017; 49(3): 1601799.
[http://dx.doi.org/10.1183/13993003.01799-2016] [PMID: 28182570]
[34]
Conradie F, Diacon AH, Ngubane N, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med 2020; 382(10): 893-902.
[http://dx.doi.org/10.1056/NEJMoa1901814] [PMID: 32130813]
[35]
Nunn AJ, Rusen ID, Van Deun A, et al. Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): Study protocol for a randomized controlled trial. Trials 2014; 15(1): 353.
[http://dx.doi.org/10.1186/1745-6215-15-353] [PMID: 25199531]
[36]
Esmail A, Oelofse S, Lombard C, et al. An all-oral 6-month regimen for multidrug-resistant tuberculosis: A multicenter, randomized controlled clinical trial (the next study). Am J Respir Crit Care Med 2022; 205(10): 1214-27.
[http://dx.doi.org/10.1164/rccm.202107-1779OC] [PMID: 35175905]
[37]
Berry C, du Cros P, Fielding K, et al. TB-PRACTECAL: Study protocol for a randomised, controlled, open-label, phase II–III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis. Trials 2022; 23(1): 484.
[http://dx.doi.org/10.1186/s13063-022-06331-8] [PMID: 35698158]
[38]
Guglielmetti L, Ardizzoni E, Atger M, et al. Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): Study protocol for an adaptive, multi-country randomized controlled trial. Trials 2021; 22(1): 651.
[http://dx.doi.org/10.1186/s13063-021-05491-3] [PMID: 34563240]
[39]
Pontali E, Sotgiu G, Tiberi S, D’Ambrosio L, Centis R, Migliori GB. Cardiac safety of bedaquiline: A systematic and critical analysis of the evidence. Eur Respir J 2017; 50(5): 1701462.
[http://dx.doi.org/10.1183/13993003.01462-2017] [PMID: 29146605]
[40]
Falzon D, Schünemann HJ, Harausz E, et al. World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur Respir J 2017; 49(3): 1602308.
[http://dx.doi.org/10.1183/13993003.02308-2016] [PMID: 28331043]
[41]
Tadolini M, Garcia-Prats AJ, D’Ambrosio L, et al. Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: Early experiences and challenges. Eur Respir J 2016; 48(3): 938-43.
[http://dx.doi.org/10.1183/13993003.00705-2016] [PMID: 27338197]
[42]
Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J 2013; 41(6): 1393-400.
[http://dx.doi.org/10.1183/09031936.00125812] [PMID: 23018916]
[43]
McKay B. New treatments for drug-resistant tb get a boost. Wall Street J 2017.
[44]
Andrey M, Emanuele P, Simon T, et al. Bedaquiline and delamanid combination treatment of 5 patients with pulmonary extensively drug-resistant tuberculosis. Emerg Infect Dis 2017; 23(10): 1718-21.
[45]
Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis. clinicaltrials.gov. https://classic.clinicaltrials.gov/ct2/show/NCT02583048 2000.
[46]
World Health Organization (WHO). Active tuberculosis drugsafety monitoring and management. 2015. Available from: http://apps.who.int/iris/bitstream/handle/10665/204465/WHO_HTM_TB_2015.28_eng.pdf?sequence=1
[47]
Dawson R, Harris K, Conradie A, et al. Efficacy of bedaquiline, pretomanid, moxifloxacin & PZA (BPaMZ) against DS-& MDR-TB. In: Conference on Retroviruses and Opportunistic Infections (CROI), CROI Foundation in partnership with the International Antiviral Society-USA, Seattle. WA. 2017.
[48]
Stagg HR, Lipman MC, McHugh TD, Jenkins HE. Isoniazid-resistant tuberculosis: A cause for concern? Int J Tuberc Lung Dis 2017; 21(2): 129-39.
[http://dx.doi.org/10.5588/ijtld.16.0716] [PMID: 28234075]
[49]
Boeree MJ, Heinrich N, Aarnoutse R, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: A multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 2017; 17(1): 39-49.
[http://dx.doi.org/10.1016/S1473-3099(16)30274-2] [PMID: 28100438]
[50]
Papineni P, Phillips P, Lu Q, Cheung YB, Nunn A, Paton N. TRUNCATE-TB: An innovative trial design for drug-sensitive tuberculosis. Int J Infect Dis 2016; 45: 404.
[http://dx.doi.org/10.1016/j.ijid.2016.02.863]
[51]
Dorman SE, Nahid P, Kurbatova EV, et al. High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemp Clin Trials 2020; 90: 105938.
[http://dx.doi.org/10.1016/j.cct.2020.105938] [PMID: 31981713]
[52]
Bouton TC, Phillips PPJ, Mitnick CD, et al. An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: Study protocol for a randomized controlled trial. Trials 2017; 18(1): 563.
[http://dx.doi.org/10.1186/s13063-017-2292-x] [PMID: 29178937]
[53]
Lee M, Mok J, Kim DK, Shim TS, Koh WJ, et al. Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (treatment shortening of MDR-TB using existing and new drugs, MDR-end): Study protocol for a phase II/III, Multicentre, randomized, Open-label clinical trial. Trials 2019; 20(1): 57.
[54]
Aung KJM, Van Deun A, Declercq E, et al. Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18(10): 1180-7.
[http://dx.doi.org/10.5588/ijtld.14.0100] [PMID: 25216831]
[55]
Piubello A, Harouna SH, Souleymane MB, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: No relapses. Int J Tuberc Lung Dis 2014; 18(10): 1188-94.
[http://dx.doi.org/10.5588/ijtld.13.0075] [PMID: 25216832]
[56]
Preliminary results from STREAM trial provide insight into shorter treatment for multidrug-resistant tuberculosis.. Available from: https://www.mrcctu.ucl.ac.uk/news/news-stories/2017/october/preliminary-results-from-stream-trial-provide-insight-into-shorter-treatment-for-multidrug-resistant-tuberculosis/
[57]
Ignatius EH, Dooley KE. New drugs for the treatment of tuberculosis. Clin Chest Med 2019; 40(4): 811-27.
[http://dx.doi.org/10.1016/j.ccm.2019.08.001] [PMID: 31731986]
[58]
Jang JG, Chung JH. Diagnosis and Treatment of Multidrug-Resistant Tuberculosis. Yeungnam University Journal of Medicine 2020; 37(4): 277-85.
[http://dx.doi.org/10.12701/yujm.2020.00626]

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