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 w...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.展开更多
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 tuberculosis.The respiratory chain is a prom...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 tuberculosis.The 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 trials.In 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 tuberculosis.Our 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.展开更多
基金supported by the National Mega-Project of China for Innovative Drugs(2019ZX09721001-003-003)the Chinese Academy of Sciences grant(154144KYSB20190005,China)+2 种基金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。
文摘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.
基金financial support from the National Natural Science Foundation of China(No.81922062)Guangdong Provincial Science and Technology Program(No.2018A050506043)and Jinan University。
文摘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 tuberculosis.The 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 trials.In 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 tuberculosis.Our 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.