Original articles
Yamin Gao, H. M. Adnan Hameed, Yang Liu, Lingmin Guo, Cuiting Fang, Xirong Tian, Zhiyong Liu, Shuai Wang, Zhili Lu, Md Mahmudul Islam, Tianyu Zhang. Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 738-749

Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans
Yamin Gaoa,b,c, H. M. Adnan Hameeda,b,c, Yang Liua,d, Lingmin Guoa,b,c, Cuiting Fanga,b,c, Xirong Tiana,d, Zhiyong Liua,c, Shuai Wanga,b,c, Zhili Lua,c, Md Mahmudul Islama,b,c, Tianyu Zhanga,b,c
a State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
b University of Chinese Academy of Sciences, Beijing 100049, China;
c Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
d Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China
Abstract:
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin—estreptomycin or rifampin—eclarithromycin daily for 8 weeks recommended by World Health Organization (WHO). These options are lengthy with severe side effects. A new anti-tuberculosis drug, TB47, targeting QcrB in cytochrome bc1:aa3 complex is being developed in China. TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M. ulcerans strain. High-level TB47-resistant spontaneous M. ulcerans mutants were selected and their qcrB genes were sequenced. The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model. Here, we show that TB47-containing oral 3-drug regimens can completely cure BU in ≤2 weeks for daily use or in ≤3 weeks given twice per week (6 doses in total). All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice. This is the first report of double mutations in QcrB in mycobacteria. In summary, TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance. Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants.
Key words:    Mycobacterium ulcerans    Buruli ulcer    Electron transport chain    QcrB    Chemotherapy    TB47    Drug resistance    Clofazimine   
Received: 2020-06-09     Revised: 2020-09-01
DOI: 10.1016/j.apsb.2020.11.007
Funds: We thank Professor Eric L. Nuermberger at Johns Hopkins University (USA) for providing us M. ulcerans strains as kind gifts for our study. We thank Dr. Xiantao Zhang, the board chairman of Guangzhou Eggbio Co. Ltd. for providing us with TB47 for the experiments. We thank the UCAS Postdoctoral Fellowship (to Hameed HMA) and CAS-TWAS President’s Ph.D. Fellowship Program (to Islam MM) for international students. Tianyu Zhang received Science and Technology Innovation Leader of Guangdong Province (2016TX03R095, China). This work was supported by the National Mega-Project of China for Innovative Drugs (2019ZX09721001-003-003), the Chinese Academy of Sciences grant (154144KYSB20190005, China), the Key-Area Research and Development Program of Guangdong Province (2019B110233003, China), the Special Funds for Economic Development of Marine Economy of Guangdong Province (GDME-2018C003, China) and partially by the Grants (SKLRD-OP-201919 and SKLRD-Z-202016) from the State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Corresponding author: Tianyu Zhang     Email:zhang_tianyu@gibh.ac.cn
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Yamin Gao
H. M. Adnan Hameed
Yang Liu
Lingmin Guo
Cuiting Fang
Xirong Tian
Zhiyong Liu
Shuai Wang
Zhili Lu
Md Mahmudul Islam
Tianyu Zhang

References:
1. van der Werf TS, van der Graaf WTA, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet 1999;354:1013-8.
2. George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, Lee R, et al. Mycolactone: A polyketide toxin from Mycobacterium ulcerans required for virulence. Science 1999;283:854-7.
3. Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsfield C, Phillips R, et al. Efficacy of the combination rifampin—streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother 2005;49:3182-6.
4. Sarfo FS, Phillips R, Asiedu K, Ampadu E, Bobi N, Adentwe E, et al. Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 2010;54:3678-85.
5. Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, et al. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. PLoS Neglected Trop Dis 2018;12: e0006728.
6. Converse PJ, Tyagi S, Xing Y, Li SY, Kishi Y, Adamson J, et al. Efficacy of rifampin plus clofazimine in a murine model of Mycobacterium ulcerans disease. PLoS Neglected Trop Dis 2015;9:e0003823.
7. Chauffour A, Robert J, Veziris N, Aubry A, Jarlier V. Sterilizing activity of fully oral intermittent regimens against Mycobacterium ulcerans infection in mice. PLoS Neglected Trop Dis 2016;10: e0005066.
8. Converse PJ, Almeida DV, Tyagi S, Xu J, Nuermberger EL. Shortening Buruli ulcer treatment with combination therapy targeting the respiratory chain and exploiting Mycobacterium ulcerans gene decay. Antimicrob Agents Chemother 2019;63:e00426-19.
9. Liu Y, Gao Y, Liu J, Tan Y, Liu Z, Chhotaray C, et al. The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model. Nat Commun 2019;10:524.
10. Wang G, Li L, Wang X, Li X, Zhang Y, Yu J, et al. Hypericin enhances beta-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus. Acta Pharm Sin B 2019; 9:1174-82.
11. Wang Q, Lv Y, Pang J, Li X, Lu X, Wang X, et al. In vitro and in vivo activity of D-serine in combination with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus. Acta Pharm Sin B 2019; 9:496-504.
12. Zhang T, Li SY, Converse PJ, Grosset JH, Nuermberger EL. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. PLoS Neglected Trop Dis 2013;7:e2598.
13. Zhang T, Bishai WR, Grosset JH, Nuermberger EL. Rapid assessment of antibacterial activity against Mycobacterium ulcerans by using recombinant luminescent strains. Antimicrob Agents Chemother 2013; 54:2806-13.
14. Dega H, Bentoucha A, Robert J, Jarlier V, Grosset J. Bactericidal activity of rifampin—amikacin against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother 2002;46:3193-6.
15. Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun 2016;7:12393.
16. Liu Y, Tan Y, Islam MM, Cao Y, Lu X, Zeng S, et al. Assessment of clofazimine and TB47 combination activity against Mycobacterium abscessus using a bioluminescent approach. Antimicrob Agents Chemother 2020;64:e01881-19.
17. Almeida D, Nuermberger EL, Tyagi S, Bishai WR, Grosset JH. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother 2007;51:4261-6.
18. Almeida D, Converse PJ, Ahmad Z, Dooley KE, Nuermberger EL, Grosset JH. Activities of rifampin, rifapentine and clarithromycin alone and in combination against Mycobacterium ulcerans disease in mice. PLoS Neglected Trop Dis 2011;5:e933.
19. Omansen TF, Almeida D, Converse PJ, Li SY, Lee J, Stienstra Y, et al. High-dose rifamycins enable shorter oral treatment in a murine model of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 2019;63. e01478-18.
20. Phillips RO, Arenaz-Callao MP, González del Río R, Lucía Quintana A, Thompson CJ, Mendoza-Losana A, et al. Triple oral betalactam containing therapy for Buruli ulcer treatment shortening. PLoS Neglected Trop Dis 2019;13:e0007126.
21. O’Brien DP, Friedman D, Hughes A, Walton A, Athan E. Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients. Intern Med J 2017;47:1011-9.
22. Williams KN, Bishai WR. Clarithromycin extended-release in community-acquired respiratory tract infections. Expet Opin Pharmacother 2006;6:2867-76.
23. Koh WJ, Jeong BH, Jeon K, Lee SY, Shin SJ. Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2012;186:797-802.
24. Wallace RJ, Brown BA, Griffith DE, William G, Ken T. Reduced serum levels of clarithromycin in patients treated with multi-drug regimens including rifampin or rifabutin for Mycobacterium aviumM. intracellulare infection. J Infect Dis 1995;3:747-50.
25. Marsollier L, Honore N, Legras P, Manceau AL, Kouakou H, Carbonnelle B, et al. Isolation of three Mycobacterium ulcerans strains resistant to rifampin after experimental chemotherapy of mice. Antimicrob Agents Chemother 2003;47:1228-32.
26. Dooley KE, Bliven-Sizemore EE, Weiner M, Lu Y, Nuermberger EL, Hubbard WC, et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther 2012;91:881-8.
27. Dorman SE, Savic RM, Goldberg S, Stout JE, Schluger N, Muzanyi G, et al. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med 2015;191: 333-43.
28. Hameed HMA, Islam MM, Chhotaray C, Wang C, Liu Y, Tan Y, et al. Molecular targets related drug resistance mechanisms in MDR-, XDR, and TDR-Mycobacterium tuberculosis strains. Front Cell Infect Microbiol 2018;8:114.
29. Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 2013;19:1157-60.
30. Lu X, Williams Z, Hards K, Tang J, Cheung CY, Aung HL, et al. Pyrazolo[1,5-α] pyridine inhibitor of the respiratory cytochrome bcc complex for the treatment of drug-resistant tuberculosis. ACS Infect Dis 2019;5:239-49.
31. Ko Y, Choi I. Putative 3D structure of QcrB from Mycobacterium tuberculosis cytochromebc1 complex, a novel drug-target for new series of antituberculosis agent Q203. Bull Kor Chem Soc 2016;37: 725-31.
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