Impact of dose, duration, and immune status on efficacy of ultrashort telacebec regimens in mouse models of buruli ulcer

Oliver Komm, Deepak V. Almeida, Paul J. Converse, Till F. Omansen, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere01418-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • Buruli ulcer
  • Mycobacterium ulcerans
  • Q203
  • Telacebec

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint

Dive into the research topics of 'Impact of dose, duration, and immune status on efficacy of ultrashort telacebec regimens in mouse models of buruli ulcer'. Together they form a unique fingerprint.

Cite this