Q203 containing fully intermittent oral regimens exhibited high sterilizing activity against Mycobacterium ulcerans in mice

Abstract

AbstractBuruli ulcer (BU), caused by Mycobacterium ulcerans is currently treated by a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate the treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine Q203 exhibited high bactericidal activity whereas tedizolid (oxazolidinone close to linezolid), selamectine and ivermectine (avermectine compound) and the benzothiazinone PBTZ169 were not active. Consequently, Q203 was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Q203 given twice a week in combination with one of the other long half-life compounds, rifapentine or bedaquiline, sterilized the mice footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after stopping the treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatments in the field.Author summaryThe current treatment of Buruli ulcer (BU), infection caused by Mycobacterium 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 on the field. We evaluated the bactericidal activity of several new antimicrobials drugs in a mice model of BU and found that the Q203 exhibited the highest bactericidal effect. We subsequently identified new antibiotic combinations containing Q203 with high sterilizing activity when administrated twice a week for 8 weeks.