Telacebec (
Q203) is a new antituberculosis
drug in clinical development that has extremely potent activity against Mycobacterium ulcerans, the causative agent of
Buruli ulcer (BU). The potency of
Q203 has prompted investigation of its potential role in ultrashort, even single-dose, treatment regimens for BU in mouse models. However, the relationships of
Q203 dose, dose schedule, duration, and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with
Q203 monotherapy. Here, we used mouse footpad
infection models in immunocompetent BALB/c and immunocompromised SCID-beige mice to compare different
Q203 doses, different dosing schedules, and treatment durations ranging from 1 day to 2 weeks, on long-term outcomes. We also tested whether combining
Q203 with a second
drug can increase efficacy. Overall, efficacy depended on total dose more than on duration. Total doses of 5 to 20 mg/kg rendered nearly all BALB/c mice culture negative by 13 to 14 weeks posttreatment, without selection of Q203-resistant bacteria. Addition of a second
drug did not significantly increase efficacy. Although less potent in SCID-beige mice,
Q203 still rendered the majority of footpads culture negative at total doses of 10 to 20 mg/kg.
Q203 resistance was identified in relapse isolates from some SCID-beige mice receiving monotherapy but not in isolates from those receiving
Q203 combined with
bedaquiline or
clofazimine. Overall, these results support the potential of
Q203 monotherapy for single-dose or other ultrashort
therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination
therapy.