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 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

作者机构：State Key Laboratory of Respiratory DiseaseGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510530China University of Chinese Academy of SciencesBeijing 100049China Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious DiseasesGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510530China Institute of Physical Science and Information TechnologyAnhui UniversityHefei 230601China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第3期

页      面：738-749页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100706[医学-药理学] 1001[医学-基础医学(可授医学、理学学位)] 100602[医学-中西医结合临床] 10[医学] 

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 

主　　题：Mycobacterium ulcerans Buruli ulcer Electron transport chain QcrB Chemotherapy TB47 Drug resistance Clofazimine 

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 ***47-containing regimens were evaluated in a well-established murine model using an autoluminescent *** *** TB47-resistant spontaneous *** mutants were selected and their qcrB genes were *** in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine ***,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 *** is the first report of double mutations in QcrB in *** summary,TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug *** 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.