Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Perspective

Repurposing Drugs to Combat Drug Resistance in Leprosy: A Review of Opportunities

Author(s): Mukul Sharma and Pushpendra Singh*

Volume 25, Issue 10, 2022

Published on: 11 January, 2022

Page: [1578 - 1586] Pages: 9

DOI: 10.2174/1386207325666211007110638

Abstract

Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries (WHO, 2019), of which nearly two-third of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy (MDT), as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in last one-decade, and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli cannot grow in vitro. Besides, developing a new drug against leprosy through conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line (MDT) and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of “leprosy-free world”. This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

Keywords: Leprosy, Mycobacterium leprae, repurposing, repositioning, antibiotic resistance, anti-leprosy drug therapy.

[1]
DeGowin, R.L. A review of therapeutic and hemolytic effects of dapsone. Arch. Intern. Med., 1967, 120(2), 242-248.
[http://dx.doi.org/10.1001/archinte.1967.00300020114017] [PMID: 4952943]
[2]
Kurien, G; Jamil, RT; Preuss, CV Dapsone. Treasure Island (FL): StatPearls Publishing.
[3]
Pettit, J.H.; Rees, R.J. Sulphone resistance in leprosy. An experimental and clinical study. Lancet, 1964, 2(7361), 673-674.
[http://dx.doi.org/10.1016/S0140-6736(64)92482-1] [PMID: 14188912]
[4]
Gupta, U.D.; Katoch, K.; Katoch, V.M. Study of rifampicin resistance and comparison of dapsone resistance of M. leprae in pre- and post-MDT era. Indian J. Lepr., 2009, 81(3), 131-134.
[PMID: 20509341]
[5]
Moet, F.J.; Pahan, D.; Oskam, L.; Richardus, J.H. Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial. BMJ, 2008, 336(7647), 761-764.
[http://dx.doi.org/10.1136/bmj.39500.885752.BE] [PMID: 18332051]
[6]
Jacobson, R.R.; Hastings, R.C. Rifampin-resistant leprosy. Lancet, 1976, 2(7998), 1304-1305.
[http://dx.doi.org/10.1016/S0140-6736(76)92071-7] [PMID: 63780]
[7]
Noordeen, S.K.; Lopez Bravo, L.; Daumerie, D. Global review of multidrug therapy (MDT) in leprosy. World Health Stat. Q., 1991, 44(1), 2-15.
[PMID: 2068821]
[8]
Cambau, E.; Perani, E.; Guillemin, I.; Jamet, P.; Ji, B. Multidrug-resistance to dapsone, rifampicin, and ofloxacin in Mycobacterium leprae. Lancet, 1997, 349(9045), 103-104.
[http://dx.doi.org/10.1016/S0140-6736(05)60888-4] [PMID: 8996430]
[9]
Warndorff-van Diepen, T. Clofazimine-resistant leprosy, a case report. Int. J. Lepr. Other Mycobact. Dis., 1982, 50(2), 139-142.
[10]
Cholo, M.C.; Steel, H.C.; Fourie, P.B.; Germishuizen, W.A.; Anderson, R. Clofazimine: current status and future prospects. J. Antimicrob. Chemother., 2012, 67(2), 290-298.
[http://dx.doi.org/10.1093/jac/dkr444] [PMID: 22020137]
[11]
Scollard, D.M.; Adams, L.B.; Gillis, T.P.; Krahenbuhl, J.L.; Truman, R.W.; Williams, D.L. The continuing challenges of leprosy. Clin. Microbiol. Rev., 2006, 19(2), 338-381.
[http://dx.doi.org/10.1128/CMR.19.2.338-381.2006] [PMID: 16614253]
[12]
Williams, D.L.; Gillis, T.P. Drug-resistant leprosy: monitoring and current status. Lepr. Rev., 2012, 83(3), 269-281.
[http://dx.doi.org/10.47276/lr.83.3.269] [PMID: 23356028]
[13]
Rosa, P.S.; D’Espindula, H.R.S.; Melo, A.C.L.; Fontes, A.N.B.; Finardi, A.J.; Belone, A.F.F.; Sartori, B.G.C.; Pires, C.A.A.; Soares, C.T.; Marques, F.B.; Branco, F.J.D.; Baptista, I.M.F.D.; Trino, L.M.; Fachin, L.R.V.; Xavier, M.B.; Floriano, M.C.; Ura, S.; Diório, S.M.; Delanina, W.F.B.; Moraes, M.O.; Virmond, M.C.L.; Suffys, P.N.; Mira, M.T. Emergence and transmission of drug-/multidrug-resistant mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clin. Infect. Dis., 2020, 70(10), 2054-2061.
[http://dx.doi.org/10.1093/cid/ciz570] [PMID: 31260522]
[14]
Saunderson, P.R. Drug-resistant M leprae. Clin. Dermatol., 2016, 34(1), 79-81.
[http://dx.doi.org/10.1016/j.clindermatol.2015.10.019] [PMID: 26773627]
[15]
Mahajan, N.P.; Lavania, M.; Singh, I.; Nashi, S.; Preethish-Kumar, V.; Vengalil, S.; Polavarapu, K.; Pradeep-Chandra-Reddy, C.; Keerthipriya, M.; Mahadevan, A.; Yasha, T.C.; Nandeesh, B.N.; Gnanakumar, K.; Parry, G.J.; Sengupta, U.; Nalini, A. Evidence for Mycobacterium leprae drug resistance in a large cohort of leprous neuropathy patients from India. Am. J. Trop. Med. Hyg., 2020, 102(3), 547-552.
[http://dx.doi.org/10.4269/ajtmh.19-0390] [PMID: 31933458]
[16]
Organization, W.H. WHO Expert Committee on Leprosy: seventh report; World Health Organization, 1998.
[17]
Pai, V.V. Second-line anti-leprosy drugs: Indian experience. Ind. J. Drugs Dermatol., 2020, 6(1), 1.
[http://dx.doi.org/10.4103/ijdd.ijdd_66_19]
[18]
Grosset, J.H. Newer drugs in leprosy. Int. J. Lepr. Other Mycobact. Dis., 2001, 69(2 Suppl.), S14-S18.
[19]
Matrat, S.; Petrella, S.; Cambau, E.; Sougakoff, W.; Jarlier, V.; Aubry, A. Expression and purification of an active form of the Mycobacterium leprae DNA gyrase and its inhibition by quinolones. Antimicrob. Agents Chemother., 2007, 51(5), 1643-1648.
[http://dx.doi.org/10.1128/AAC.01282-06] [PMID: 17325221]
[20]
Sturgill, M.G.; Rapp, R.P. Clarithromycin: review of a new macrolide antibiotic with improved microbiologic spectrum and favorable pharmacokinetic and adverse effect profiles. Ann. Pharmacother., 1992, 26(9), 1099-1108.
[http://dx.doi.org/10.1177/106002809202600912] [PMID: 1421677]
[21]
Gelber, R.H. Activity of minocycline in Mycobacterium leprae-infected mice. J. Infect. Dis., 1987, 156(1), 236-239.
[http://dx.doi.org/10.1093/infdis/156.1.236] [PMID: 3298454]
[22]
Overview of antibiotic therapy: AMBOSS Available from: https://www.amboss.com/us/knowledge/Overview_of_antibiotic_therapy
[23]
Ioerger, T.R.; O’Malley, T.; Liao, R.; Guinn, K.M.; Hickey, M.J.; Mohaideen, N.; Murphy, K.C.; Boshoff, H.I.; Mizrahi, V.; Rubin, E.J.; Sassetti, C.M.; Barry, C.E., III; Sherman, D.R.; Parish, T.; Sacchettini, J.C. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One, 2013, 8(9), e75245.
[http://dx.doi.org/10.1371/journal.pone.0075245] [PMID: 24086479]
[24]
Miggiano, R.; Morrone, C.; Rossi, F.; Rizzi, M. Targeting genome integrity in Mycobacterium tuberculosis: from nucleotide synthesis to DNA replication and repair. Molecules, 2020, 25(5), E1205.
[http://dx.doi.org/10.3390/molecules25051205] [PMID: 32156001]
[25]
Wang, F.; Langley, R.; Gulten, G.; Dover, L.G.; Besra, G.S.; Jacobs, W.R., Jr; Sacchettini, J.C. Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med., 2007, 204(1), 73-78.
[http://dx.doi.org/10.1084/jem.20062100] [PMID: 17227913]
[26]
Burgos, J.; de la Cruz, E.; Paredes, R.; Andaya, C.R.; Gelber, R.H. The activity of several newer antimicrobials against logarithmically multiplying M. leprae in mice. Lepr. Rev., 2011, 82(3), 253-258.
[http://dx.doi.org/10.47276/lr.82.3.253] [PMID: 22125933]
[27]
Shuxian, H.; Wang, X.; Liyuan, C.; Kai, J.; Zhang, H. Drug for killing acid-fast (red) bacillus; Google Patents, 2017.
[28]
Pechalrieu, D.; Lopez, M. Compounds for use in the treatment of mycobacterial infections: A patent evaluation (WO2014049107A1). Expert Opin. Ther. Pat., 2015, 25(6), 729-735.
[http://dx.doi.org/10.1517/13543776.2015.1021333] [PMID: 25752488]
[29]
Galatsis, P.; Hayward, M.M.; Kormos, B.L.; Wager, T.T.; Zhang, L.; Henderson, J.L. 3, 4-disubstituted-1 H-pyrrolo [2, 3-b] pyridines and 4, 5-disubstituted-7H-pyrrolo [2, 3-c] pyridazines as LRRK2 inhibitors. In: Google Patents;; , 2017.
[30]
Galatsis, P.; Hayward, M.M.; Kormos, B.L.; Wager, T.T.; Zhang, L.; Stepan, A.F. 4-(substituted amino)-7H-pyrrolo [2, 3-d] pyrimidines as LRRK2 inhibitors. In: Google Patents; , 2015.
[31]
D’angio, P.; McCarty, J. Pharmaceutical compositions and dosage forms of thalidomide; Google Patents, 2015.
[32]
Benigni, F.; D’ambrosio, D. Anti-TrkA antibodies and derivatives thereof; Google Patents, 2013.
[33]
Munir, A.; Vedithi, S.C.; Chaplin, A.K.; Blundell, T.L. Genomics, computational biology and drug discovery for mycobacterial infections: fighting the emergence of resistance. Front. Genet., 2020, 11, 965.
[http://dx.doi.org/10.3389/fgene.2020.00965] [PMID: 33101362]
[34]
Gillini, L.; Cooreman, E.; Wood, T.; Pemmaraju, V.R.; Saunderson, P. Global practices in regard to implementation of preventive measures for leprosy. PLoS Negl. Trop. Dis., 2017, 11(5), e0005399.
[http://dx.doi.org/10.1371/journal.pntd.0005399] [PMID: 28472183]
[35]
Van’t Noordende, A.T.; Lisam, S.; Ruthindartri, P.; Sadiq, A.; Singh, V.; Arifin, M.; van Brakel, W.H.; Korfage, I.J. Leprosy perceptions and knowledge in endemic districts in India and Indonesia: Differences and commonalities. PLoS Negl. Trop. Dis., 2021, 15(1), e0009031.
[http://dx.doi.org/10.1371/journal.pntd.0009031] [PMID: 33476343]
[36]
Govindasamy, K.; Jacob, I.; Solomon, R.M.; Darlong, J. Burden of depression and anxiety among leprosy affected and associated factors-A cross sectional study from India. PLoS Negl. Trop. Dis., 2021, 15(1), e0009030.
[http://dx.doi.org/10.1371/journal.pntd.0009030] [PMID: 33481790]
[37]
Waman, V.P.; Vedithi, S.C.; Thomas, S.E.; Bannerman, B.P.; Munir, A.; Skwark, M.J.; Malhotra, S.; Blundell, T.L. Mycobacterial genomics and structural bioinformatics: opportunities and challenges in drug discovery. Emerg. Microbes Infect., 2019, 8(1), 109-118.
[http://dx.doi.org/10.1080/22221751.2018.1561158] [PMID: 30866765]

© 2024 Bentham Science Publishers | Privacy Policy