Open Access Open Access  Restricted Access Subscription Access

Increscent Journey of Anti-Leprosy Drug Development


Affiliations
1 Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
2 Department of Biotechnology, GLA University, NH-2, Mathura-Delhi Road, Mathura 281 406, India
 

Leprosy, a chronic granulomatous disease generally caused by Mycobacterium leprae and Mycobacterium lepromatosis, remains a serious public health concern, particularly in developing countries. With the introduction of multi-drug therapy (MDT) by the World Health Organization in 1980, the prevalence of leprosy has declined globally. In the past, acid-fast bacilli frequently developed resistance to both first-line (dapsone, rifampicin and clofazimine) and second-line drugs (fluoroquinolones, minocycline and clarithromycin). According to previous research, it is reported that genes like rpoB, gyrA and folP play a role in drug resistance. Considering its exceptionally modest pace of growth, it is challenging to cultivate M. leprae in a laboratory environment on a synthetic medium. Thus, studies on animal models have assisted in evaluating anti-leprosy drugs and documentation of drug-resistant strains, as well as other basic immunological investigations examining the efficacy of vaccinations. In addition to the conventionally administered MDT treatments, several newly developed drugs have shown more impressive results, along with combinational therapies of moxifloxacin-based regimens, having much better efficacy. This review focuses on the increscent journey of anti-leprosy drugs to treat the disease and highlights the relevance of animal models in the research and development of anti-leprosy drugs.

Keywords

Animal Models, Antibiotic, Drugs-Mode of Action, Mycobacterium leprae, Pharmacokinetics, Vaccine.
User
Notifications
Font Size

  • Han, X. Y., Sizer, K. C., Velarde-Félix, J. S., Frias-Castro, L. O. and Vargas-Ocampo, F., The leprosy agents Mycobacterium lepromatosis and Mycobacterium leprae in Mexico. Int. J. Dermatol., 2012, 51, 952–959.
  • Gillis, T. P., Mycobacterium leprae. In Molecular Medical Micro-biologyt, Elsevier Ltd, London, 2014, 2nd edn.
  • Palit, A. and Kar, H. K., Prevention of transmission of leprosy: the current scenario. Indian J. Dermatol. Venereol. Leprol., 2020, 86, 115–123.
  • Gillis, T. P. and Williams, D. L., Dapsone resistance in Mycobacterium leprae. Lepr. Rev., 2000, 71, 91–95.
  • Honore, N. C. S., Molecular basis of Rifampin resistance in Myco-bacterium leprae. Antimicrob. Agents Chemother., 1993, 37, 414–418.
  • Veziris, N. et al., Resistance of M. leprae to Quinolones: a question of relativity? PLoS Negl. Trop. Dis., 2013, 7, 1–5.
  • Matsuoka, M., Global surveillance system to monitor the development of drug resistance in Mycobacterium leprae. Res. Rep. Trop. Med., 2015, 6, 75–83.
  • Pandhi, D. and Chhabra, N., New insights in the pathogenesis of type 1 and type 2 lepra reaction. Indian J. Dermatol. Venereol. Leprol., 2013, 79, 739–749.
  • Ebenezer, G. J. and Scollard, D. M., Treatment and evaluation advances in leprosy neuropathy. Neurotherapeutics, 2021, 18, 2337–2350.
  • Yamaguchi, T., Yokoyama, K., Nakajima, C. and Suzuki, Y., DC-159a shows inhibitory activity against DNA Gyrases of Mycobacterium leprae. PLoS Negl. Trop. Dis., 2016, 10, 1–13.
  • Gautam, S., Sharma, D., Goel, A., Patil, S. A. and Bisht, D., Insights into Mycobacterium leprae proteomics and biomarkers – an overview. Proteomes, 2021, 9, 1–18.
  • Ridley, D. S. and Jopling, W. H., Classification of leprosy according to immunity. A five-group system. Int. J. Lepr. Other Mycobact. Dis., 1966, 34, 255–273.
  • WHO, Chemotherapy of Leprosy for Control Programmes, World Health Organization – Technical Report, Services, 1982.
  • Arif, T., Dorjay, K., Adil, M. and Sami, M., Classification of leprosy – from past to present. J. Pak. Assoc. Dermatol., 2018, 28, 95–99.
  • Johnstone, P. A., The search for animal models of leprosy. Int. J. Lepr. Other Mycobact. Dis., 1987, 55, 535–547.
  • Shepard, C. C., The experimental disease that follows the injection of human leprosy bacilli into foot-pads of mice. J. Exp. Med., 1960, 112, 445–454.
  • Kirchheimer, W. F. and Storrs, E. E., Attempts to establish the armadillo (Dasypus novemcinctus Linn.) as a model for the study of leprosy. I. Report of lepromatoid leprosy in an experimentally infected armadillo. Int. J. Lepr. Other Mycobact. Dis., 1971, 39, 693–702.
  • Truman, R. W. et al., The armadillo as a model for peripheral neuropathy in leprosy. ILAR J., 2014, 54, 304–314.
  • Scollard, D. M., Adams, L. B., Gillis, T. P., Krahenbuhl, J. L., Truman, R. W. and Williams, D. L., The continuing challenges of leprosy. Clin. Microbiol. Rev., 2006, 19, 338–381.
  • Vera-cabrera, L. et al., Mycobacterium leprae infection in a wild nine banded armadillo Nuevo Leon, Mexico. Emerg. Infect. Dis., 2022, 27, 27–29.
  • Duthie, M. S. et al., LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection. npj Vaccines, 2018, 3.
  • Adams, L. B., Susceptibility and resistance in leprosy: studies in the mouse model. Immunol. Rev., 2021, 301, 157–174.
  • Kim, I. K., The trend of leprosy treatment. Korean Lepr. Bull., 2015, 48, 13–15.
  • Dogra, S., Narang, T. and Kumar, B., Leprosy – evolution of the path to eradication. Indian J. Med. Res., 2013, 137, 15–35.
  • Sahoo, M. R. et al., Hydnocarpus: an ethnopharmacological, phyto-chemical and pharmacological review. J. Ethnopharmacol., 2014, 154, 17–25.
  • Faget, G. H., Pogge, R. C., Johansen, F. A., Dinan, J. F., Prejean, B. M. and Eccles, C. G., The promin treatment of leprosy. A progress report. Int. J. Lepr. Other Mycobact. Dis., 1966, 34, 298–310.
  • Wozel, G. and Blasum, C., Dapsone in dermatology and beyond. Arch. Dermatol. Res., 2014, 306, 103–124.
  • Coleman, M. D., Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br. J. Dermatol., 1993, 129, 507–513.
  • Pieters, F. A. and Zuidema, J., The absolute oral bioavailability of dapsone in dogs and humans. Int. J. Clin. Pharmacol. Ther. Toxicol., 1987, 25, 396–400.
  • Zhu, Y. I. and Stiller, M. J., Dapsone and sulfones in dermatology: overview and update. J. Am. Acad. Dermatol., 2001, 45, 420–434.
  • Zuidema, J., Hilbers-Modderman, E. S. M. and Merkus, F. W. H. M., Clinical pharmacokinetics of dapsone. Clin. Pharmacokinet., 1986, 11, 299–315.
  • Tian, W., Shen, J., Zhou, M., Yan, L. and Zhang, G., Dapsone hypersensitivity syndrome among leprosy patients in China. Lepr. Rev., 2012, 83, 370–377.
  • Venkatesan, K., Clinical pharmacokinetic considerations in the treatment of Patients with leprosy. Clin. Pharmacokinet., 1989, 16, 365–386.
  • Kar, H. K. and Gupta, R., Treatment of leprosy. Clin. Dermatol., 2015, 33, 55–65.
  • Nakata, N., Kai, M. and Makino, M., Mutation analysis of the Mycobacterium leprae folP1 gene and dapsone resistance. Antimicrob. Agents Chemother., 2011, 55, 762–766.
  • Nisha, J., Ramanathan, K., Nawaz Khan, F., Dhanasekaran, D. and Shanthi, V., Discovery of a potential lead compound for treating leprosy with dapsone resistance mutation in M. leprae folP1. Mol. Biosyst., 2016, 12, 2178–2188.
  • McClure, W. R. and Cech, C. L., On the mechanism of rifampicin inhibition of RNA synthesis. J. Biol. Chem., 1978, 253, 8949–8956.
  • Acocella, G., Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet., 1978, 3, 108–127.
  • Cambau, E. et al., Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by a WHO surveillance network for the period 2009–15. Clin. Microbiol. Infect., 2018, 24, 1305–1310.
  • Richardus, J. H. et al., Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme. Lancet Glob. Heal., 2021, 9, e81–e90.
  • Riccardi, N. et al., Clofazimine: an old drug for never-ending diseases. Future Microbiol., 2020, 15, 557–566.
  • Cholo, M. C., Steel, H. C., Fourie, P. B., Germishuizen, W. A. and Anderson, R., Clofazimine: current status and future prospects. J. Antimicrob. Chemother., 2012, 67, 290–298.
  • Singh, H., Azad, K. and Kaur, K., Clofazimine-induced enteropathy in a patient of leprosy. Indian J. Pharmacol., 2013, 45, 197–199.
  • Morrison, N. E. and Marley, G. M., Clofazimine binding studies with deoxyribonucleic acid. Int. J. Lepr. Other Mycobact. Dis., 1976, 44, 475–481.
  • Ren, Y. R. et al., Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS ONE, 2008, 3, 1–11.
  • Feng, P. C., Fenselau, C. C. and Jacobson, R. R., Metabolism of clofazimine in leprosy patients. Drug Metab. Dispos., 1981, 9, 521–524.
  • Yuan, S. et al., Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature, 2021, 593, 418–423.
  • Alangaden, G. J. and Lerner, S. A., The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. Clin. Infect. Dis., 1997, 25, 1213–1221.
  • Hooper, D. C. and Jacoby, G. A., Topoisomerase inhibitors: fluoroquinolone mechanisms of action and resistance. Cold Spring Harb. Perspect. Med., 2016, 6, 1–21.
  • Dalhoff, A., Pharmacodynamics of fluoroquinolones. J. Antimicrob. Chemother., 1999, 43, 51–59.
  • Venkatesan, K., Pharmacokinetics and drug interactions of newer anti-leprosy drugs. Indian J. Dermatol. Venereol. Leprol., 1997, 63, 148–152.
  • Sales-Marques, C. et al., Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy. PLoS Negl. Trop. Dis., 2017, 11, 1–16.
  • Raharolahy, O. et al., A case of fluoroquinolone-resistant leprosy discovered after 9 years of misdiagnosis. Case Rep. Infect. Dis., 2016, 2016, 1–4.
  • Pai, V. V., Second line anti-leprosy drugs: Indian experience. Indian J. Drugs Dermatol., 2020, 6, 1–4.
  • Narang, T., Arshdeep and Dogra, S., Minocycline in leprosy patients with recent onset clinical nerve function impairment. Dermatol. Ther., 2017, 30, 1–4.
  • Ji, B., Perani, E. G. and Grosset, J. H., Effectiveness of clarithromycin and minocycline alone and in combination against experimental Mycobacterium leprae infection in mice. Antimicrob. Agents Chemother., 1991, 35, 579–581.
  • Taylor, E. D. and Cahu, A., Tetracycline resistance mediated by ribosomal protection. Antimicrob. Agents Chemother., 1996, 40, 1–5.
  • Williams, D. L. and Gillis, T. P., Drug-resistant leprosy: monitoring and current status. Lepr. Rev., 2012, 83, 269–281.
  • Saivin, S. and Houin, G., Clinical pharmacokinetics of doxycycline and minocycline. Clin. Pharmacokinet., 1988, 15, 355–366.
  • Nelis, H. J. and De Leenheer, A. P., Metabolism of minocycline in humans. Drug Metab. Dispos., 1982, 10, 142–146.
  • Vester, B. and Douthwaite, S., Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob. Agents Chemother., 2001, 45, 1–12.
  • Arikata, M. et al., Efficacy of clarithromycin against H5N1 and H7N9 avian influenza a virus infection in cynomolgus monkeys. Antiviral Res., 2019, 171, 1–6.
  • Gunawan, H., Sasmojo, M., Putri, H. E., Avriyanti, E., Hindritiani, R. and Suwarsa, O., Clarithromycin efficacy in multibacillary leprosy therapy. Int. J. Mycobacteriol., 2018, 7, 152–155.
  • WHO, Chemotherapy of Leprosy, Report of a WHO Study Group, World Health Organization, Geneva, Switzerland, 1993.
  • WHO, WHO Expert Committee on Leprosy: Seventh report. World Health Organization, Geneva, Switzerland, 1998.
  • WHO, Multi-drug Therapy Against Leprosy: Development and Implementation over the past 25 years, World Health Organization, 2004.
  • Anusuya, S. and Natarajan, J., Multi-targeted therapy for leprosy: in silico strategy to overcome multi drug resistance and to improve therapeutic efficacy. Infect. Genet. Evol., 2012, 12, 1899–1910.
  • Manickam, P. et al., International open trial of uniform multidrug therapy regimen for leprosy patients: findings and implications for national leprosy programmes. Indian J. Med. Res., 2016, 144, 525–535.
  • Tiendrebeogo, A., Andriamiandrisoa, M., Vololoarinosinjatovo, M. M., Andrianarisoa, S. H., Randriamitantsoa, J. and Bide, L., Evaluation of accompanied MDT (AMDT) in Madagascar. Commun. Dis. Bull. African Reg., 2004, 2, 5–8.
  • Malathi, M. and Thappa, D. M., Fixed-duration therapy in leprosy: limitations and opportunities. Indian J. Dermatol., 2013, 58, 93–100.
  • Bailey, M. A., Na, H., Duthie, M. S., Gillis, T. P., Lahiri, R. and Parish, T., Nitazoxanide is active against Mycobacterium leprae. PLoS ONE, 2017, 12, 1–9.
  • Duthie, M. S., Gillis, T. P. and Reed, S. G., Advances and hurdles on the way toward a leprosy vaccine. Hum. Vaccin., 2011, 7, 1172–1183.
  • Geluk, A. et al., New biomarkers with relevance to leprosy diagnosis applicable in areas hyperendemic for leprosy. J. Immunol., 2012, 188, 4782–4791.
  • Fischer, E. A. J., de Vlas, S. J., Habbema, J. D. F. and Richardus, J. H., The long term effect of current and new interventions on the new case detection of leprosy: a modeling study. PLoS Negl. Trop. Dis., 2011, 5, e1330.
  • Steinmann, P., Reed, S. G., Mirza, F., Hollingsworth, T. D. and Richardus, J. H., Innovative tools and approaches to end the transmission of Mycobacterium leprae. Lancet Infect. Dis., 2017, 17, e298–e305.
  • Gormus, B. J. and Meyers, W. M., Under-explored experimental topics related to integral mycobacterial vaccines for leprosy. Expert Rev. Vaccines, 2003, 2, 791–804.
  • Gupte, M. D., Indian J. Lepr., 1998, 70, 369–388.
  • Sharma, P. et al., Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients: clinical field trials with a follow up of 8–10 years. Lepr. Rev., 2005, 76, 127–143.
  • Singh, N. B., Lowe, A. C. R. E., Rees, R. J. W. and Colston, M. J., Vaccination of mice against Mycobacterium leprae infection. Infect. Immun., 1989, 57, 653–655.
  • Singh, N. B., Srivastava, A., Gupta, H. P. and Kumar, A. S. S., Induction of lepromin positivity in monkeys by a candidate antileprosy vaccine: Mycobacterium habana. Int. J. Lepr. Other Mycobact. Dis., 1991, 59, 317–320.
  • Wakhlu, A., Gaur, S. P., Kaushal, G. P., Misra, A., Asthana, P. and Sircar, A. R., Response of Mycobacterium habana vaccine in patients with lepromatous leprosy and their household contacts. A pilot clinical study. Lepr. Rev., 2001, 72, 179–191.
  • Duthie, M. S., Casper, C. and Reed, S. G., Second coming: the re-emergence and modernization of immunotherapy by vaccines as a component of leprosy control. Future Microbiol., 2018, 13, 1449–1451.
  • Craig, J., MacRae, C., Melvin, R. G. and Boggild, A. K., Case report: a case of type 1 leprosy reaction and dapsone hypersensitivity syndrome complicating the clinical course of multibacillary leprosy. Am. J. Trop. Med. Hyg., 2019, 100, 1145–1148.
  • Girling, D. J. and Hitze, K. L., Adverse reactions to rifampicin. Bull. World Health Organ., 1979, 57, 45–49.
  • Garrelts, J. C., Clofazimine: a review of its use in leprosy. Ann. Pharmacother., 1991, 25, 525–531.
  • Mathews, B., Thalody, A. A., Miraj, S. S., Kunhikatta, V., Rao, M. and Saravu, K., Adverse effects of fluoroquinolones: a retrospective cohort study in a South Indian tertiary healthcare facility. Antibiotics, 2019, 8, 1–17.
  • Martins, A. M., Marto, J. M., Johnson, J. L. and Graber, E. M., A review of systemic minocycline side effects and topical minocycline as a safer alternative for treating acne and rosacea. Antibiotics, 2021, 10, 1–23.
  • Şengeze, N., Yürekli, V. A., Koyuncuoğlu, H. R. and Kırbaş, S., Permanent taste and smell disorders induced by clarithromycin: a case report. Türk. Nöroloi Derg., 2015, 21, 34–36.
  • Wani, G. H. M. U. D., Lone, S. U. D., Khursheed, B., Sayeed, S. I. and Wani, H. A., Clinical evaluation of multibacillary leprosy patients after fixed duration multidrug therapy (FD-MDT) of one year: a hospital based study. Indian J. Sci. Res., 2018, 4, 603–606.
  • Ji, B. and Grosset, J., Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy. Lepr. Rev., 2000, 71, S81–S87.
  • Ebenezer, G. J. and Job, C. K., Histopathological activity in paucibacillary leprosy patients after ROM therapy.pdf. Int. J. Lepr. Other Mycobact. Dis., 1999, 67, 409–413.
  • Kumar, A. G. B., Multibacillary leprosy: follow up observations on 19 patients treated with 12 monthly doses of rifampicin, ofloxacin and minocycline therapy in Agra. Indian J. Dermatol. Venereol. Leprol., 2014, 80, 155–159.
  • Khang, T. H., Panikar, V., Lanh, P. H., Minh, T. T. and Hai, P. H., Treatment of leprosy with ofloxacin – containing combined drug regimens in Vietnam. Madridge J. Dermatol. Res., 2019, 4, 96–99.
  • Vivekkumar, S. P. et al., Levofloxacin (L-Ofloxacin) in paucibacillary leprosy. Glob. J. Pharmacol., 2010, 4, 117–121.
  • Pardillo, F. E. F. et al., Powerful bactericidal activity of moxifloxacin in human leprosy. Antimicrob. Agents Chemother., 2008, 52, 3113–3117.
  • Ji, B., Chauffour, A., Andries, K. and Jarlier, V., Bactericidal activities of R207910 and other newer antimicrobial agents against Mycobacterium leprae in mice. Antimicrob. Agents Chemother., 2006, 50, 1558–1560.
  • Dhople, A. M., In vitro activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with brodimoprim and dapsone, against Mycobacterium leprae. Int. J. Antimicrob. Agents, 1999, 12, 319–323.
  • Chan, G. P. et al., Clinical trial of Sparfloxacin for lepromatous leprosy. Antimicrob. Agents Chemother., 1994, 38, 61–65.
  • Franzblau, S. G. et al., Clinical trial of fusidic acid for lepromatous leprosy. Antimicrob. Agents Chemother., 1994, 38, 1651–1654.
  • Gelber, R. H., The activity of amoxicillin plus clavulanic acid against Mycobacterium leprae in mice. J. Infect. Dis., 1991, 163, 1374–1377.
  • Ji, B. et al., Antimycobacterial activities of two newer ansamycins, R-76-1 and DL 473. Int. J. Lepr., 1986, 54, 563–577.

Abstract Views: 226

PDF Views: 91




  • Increscent Journey of Anti-Leprosy Drug Development

Abstract Views: 226  |  PDF Views: 91

Authors

Sakshi Gautam
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
Devesh Sharma
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
Sakshi Singh
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
Nirmala Deo
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
Anjana Goel
Department of Biotechnology, GLA University, NH-2, Mathura-Delhi Road, Mathura 281 406, India
Vivek Kumar Gupta
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India
Deepa Bisht
Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj 282 001, India

Abstract


Leprosy, a chronic granulomatous disease generally caused by Mycobacterium leprae and Mycobacterium lepromatosis, remains a serious public health concern, particularly in developing countries. With the introduction of multi-drug therapy (MDT) by the World Health Organization in 1980, the prevalence of leprosy has declined globally. In the past, acid-fast bacilli frequently developed resistance to both first-line (dapsone, rifampicin and clofazimine) and second-line drugs (fluoroquinolones, minocycline and clarithromycin). According to previous research, it is reported that genes like rpoB, gyrA and folP play a role in drug resistance. Considering its exceptionally modest pace of growth, it is challenging to cultivate M. leprae in a laboratory environment on a synthetic medium. Thus, studies on animal models have assisted in evaluating anti-leprosy drugs and documentation of drug-resistant strains, as well as other basic immunological investigations examining the efficacy of vaccinations. In addition to the conventionally administered MDT treatments, several newly developed drugs have shown more impressive results, along with combinational therapies of moxifloxacin-based regimens, having much better efficacy. This review focuses on the increscent journey of anti-leprosy drugs to treat the disease and highlights the relevance of animal models in the research and development of anti-leprosy drugs.

Keywords


Animal Models, Antibiotic, Drugs-Mode of Action, Mycobacterium leprae, Pharmacokinetics, Vaccine.

References





DOI: https://doi.org/10.18520/cs%2Fv125%2Fi3%2F253-267