Telacebec for ultrashort treatment of Buruli ulcer in a mouse model

Deepak V. Almeida, Paul Converse, Till F. Omansen, Sandeep Tyagi, Rokeya Tasneen, Jeongjun Kim, Eric L. Nuermberger

Research output: Contribution to journalArticle

Abstract

Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for > 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to < 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Original languageEnglish (US)
Article numbere00259-20
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Buruli ulcer
  • Mycobacterium ulcerans
  • Q203
  • Telacebec

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Almeida, D. V., Converse, P., Omansen, T. F., Tyagi, S., Tasneen, R., Kim, J., & Nuermberger, E. L. (2020). Telacebec for ultrashort treatment of Buruli ulcer in a mouse model. Antimicrobial agents and chemotherapy, 64(6), [e00259-20]. https://doi.org/10.1128/AAC.00259-20