Telacebec (Q203)-containing intermittent oral regimens sterilized mice infected with Mycobacterium ulcerans after only 16 doses

Buruli ulcer (BU), caused byMycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials againstM.ulceransusing a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field. Author summary The current treatment for Buruli ulcer (BU), an infection caused byMycobacterium ulcerans, is based on a daily antibiotic combination of rifampin associated with streptomycin or clarithromycin. A shorter or intermittent treatment without an injectable drug would clearly simplify the management in the field. We evaluated the bactericidal activity of several new antimicrobial drugs in a mouse model of BU and found that telacebec (Q203) exhibited the greatest bactericidal effect. We subsequently identified new antibiotic combinations containing telacebec with high sterilizing activity when administered twice a week for 8 weeks, i.e. at a total of only 16 doses.