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  

作　　者：Yamin Gao HMAdnan Hameed Yang Liu Lingmin Guo Cuiting Fang Xirong Tian Zhiyong Liu Shuai Wang Zhili Lu Md Mahmudul Islam Tianyu Zhang 

机构地区：[1]State Key Laboratory of Respiratory Disease,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China [4]Institute of Physical Science and Information Technology,Anhui University,Hefei 230601,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第3期738-749,共12页药学学报（英文版）

基　　金：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);partially by the Grants(SKLRDOP-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。

摘　　要：Buruli ulcer(BU),caused by Mycobacterium ulcerans,is currently treated with rifampin estreptomycin or rifampineclarithromycin 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.Highlevel 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.

关 键 词：Mycobacterium ulcerans Buruli ulcer Electron transport chain QcrB Chemotherapy TB47 Drug resistance CLOFAZIMINE 

分 类 号：R965[医药卫生—药理学]