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

Abstract

Buruli ulcer (BU), caused by Mycobacterium 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 against M. ulcerans using 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.

Fig 1

Images representative of the lesion indexes used (A) index 0; (B) index 1; (C) index 2; (D) index 3; (E) index 4. Measure of the index was taken at the middle of the footpad (see the black bracket). Measures of indexes were as follows: 2mm for index 0; 3mm for index 1; 4.5mm for index 2; 5.5mm for index 3; and 6.5mm for index 4.

Fig 2. First experiment: Mean lesion index of M. ulcerans-infected mouse footpads during treatment for 8 weeks.

Doses were as follow: rifampin (RIF), 10 mg/kg; streptomycin (STR), 150 mg/kg; tedizolid (TDZ), 10 mg/kg; linezolid (LZD), 100 mg/kg; selamectin (SEL), 12 mg/kg; ivermectin (IVE), 1 mg/kg; telacebec (Q203), 5 mg/kg; PBTZ169 (PBTZ), 25 mg/kg. The number of doses/number of weeks for RIF alone were 5/7; for RIF-STR, 5/7; for TDZ, 5/7; for LZD, 5/7; for SEL, 1/7; for IVE, 5/7; for Q203, 5/7 and for PBTZ, 5/7.

Fig 3. Second experiment: Mean lesion index of M. ulcerans-infected mouse footpads during and after treatment for 8 weeks.

Dosages were as follows: rifampin (RIF), 10 mg/kg; rifapentine (RPT), 20 mg/kg; bedaquiline (BDQ), 25 mg/kg; Q203, 5 mg/kg; clarithromycin (CLR), 100 mg/kg. RIF was given (n of doses/n of weeks) 5/7; RPT, 2/7; BDQ, 2/7; Q203, 2/7 or 5/7; RIF-CLR, 5/7; Q203-RIF, 5/7; Q203-BDQ, 2/7 and Q203-RPT, 2/7. 1.2–1.3 at week 8 and remained at that level until week 28.