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New antituberculosis drugs targeting the respiratory chain

Chinese Chemical Letters 2020年第6期31卷 1357-1365,F0003页

作者： Qian Li Xiaoyun Lu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE) School of PharmacyJi'nan UniversityGuangzhou 510632China

With the emergence of multidrug-resistant tuberculosis and extensive drug-resistant tuberculosis strains,there is an urgent need to develop novel drugs for the treatment of *** respiratory chain is a promising target for the development of newantimycobacterial agents,and a growing number of compounds have been reported and some have entered clinical *** this review,we summarize the main features and the electron transfer process of the mycobacterial respiratory chain,and the recent progress in the search for new small molecule inhibitors to rgeting the three main potential targets in the respiratory chain of Mycrobacterium *** emphasis is on the optimization strategy of qcrb inhibitors and the challenges of developing qcrb inhibitors as antituberculosis drugs due to the alternate bd-type oxidase oxidative compensation pathway are discussed.

关键词： Respiratory chain Antituberculosis drug qcrb NADH-2 ATP synthase

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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

引用

Acta Pharmaceutica Sinica B 2021年第3期11卷 738-749页

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 State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510530China University of Chinese Academy of Sciences Beijing 100049China Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou 510530China Institute of Physical Science and Information Technology Anhui UniversityHefei 230601China

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.

关键词： Mycobacterium ulcerans Buruli ulcer Electron transport chain qcrb Chemotherapy TB47 Drug resistance Clofazimine

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