Impact of dose, duration and host immune status on ultrashort telacebec treatment in a mouse model of Buruli ulcer

Abstract

ABSTRACTTelacebec (Q203) is a new anti-tuberculosis drug in clinical development with 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 ultra-short, even single-dose, treatment regimens for BU in mouse models. However, the relationships of Q203 dose and duration and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with Q203 monotherapy. In the present study, immunocompetent BALB/c and immunocompromised SCID-beige mice were infected in both hind footpads and treated eight weeks later. In both mouse strains, controls received rifampin-clarithromycin; others received Q203 at 0.5 or 2 mg/kg/d for 5 or 10 days. Additionally, BALB/c mice received a single dose of 2.5 or 10 mg/kg or 3.3 mg/kg/d for 3 days. Treatment response was based on changes in footpad swelling and CFU counts at the end of treatment as well as 4 and 13 weeks after stopping treatment. Efficacy depended on total dose more than duration. Total doses of 5-20 mg/kg rendered nearly all BALB/c mice culture-negative 13 weeks post-treatment without selection of Q203-resistant bacteria. Although less potent in SCID-beige mice, Q203 still rendered the majority of footpads culture-negative at total doses of 10-20 mg/kg. However, Q203 resistance was identified in relapse isolates from some SCID-beige mice. Overall, these results support the potential of Q203 monotherapy for single-dose or other ultra-short therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination therapy.