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

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.