Buruli ulcer is treatable with
antibiotics. An 8-week course of
rifampin (RIF) and either
streptomycin (STR) or
clarithromycin (CLR) cures over 90% of patients. However, STR requires
injections and may be toxic, and CLR shares an adverse
drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad
infection model showed that increasing the dose of RIF or using the long-acting
rifamycin rifapentine (RPT), in combination with
clofazimine (CFZ), a relatively well-tolerated
antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce
reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the
ATP synthase inhibitor
bedaquiline (BDQ) and the bc1:aa3
oxidase inhibitor
Q203 (now named
telacebec), was recently described against Mycobacterium tuberculosis Recognizing that M.
tuberculosis mutants lacking the alternative bd
oxidase are hypersusceptible to
Q203 and that Mycobacterium ulcerans is a natural bd
oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to
Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ,
Q203, and/or BDQ in a mouse footpad model. The MIC of
Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and
Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with
Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.