Repurposing drugs to advance the treatment of Buruli ulcer.

Abstract

Aligned with the World Health Organization's Road Map, there is an unmet need for research to improve the treatment of Buruli ulcer caused by Mycobacterium ulcerans. The repurposing of drugs could speed up new regimen development to treat Buruli ulcer. Using a virulent reporter strain of M. ulcerans with intrinsic bioluminescence (MuAL), we compared the minimum inhibitory concentration (MIC) of moxifloxacin, bedaquiline, telacebec, tebipenem, omadacycline, and epetraborole with standard-of-care drugs-rifampin and clarithromycin. We also compared the efficacy (maximal kill or E_max) and potency (EC₅₀ or concentration associated with 50% of E_max) as single and two-drug combinations. The doubling time of MuAL was calculated as 3.66 (95% CI: 3.41-3.93) days. Telacebec had the lowest MIC (0.0000075 mg/L) among the eight drugs tested, followed by rifampicin (0.5 mg/L) and clarithromycin (0.5 mg/L). Epetraborole, telacebec, and moxifloxacin monotherapy at tested concentrations showed higher E_max compared to clarithromycin and rifampicin. In preclinical studies, telacebec combined with rifampicin or epetraborole and epetraborole combinations with moxifloxacin and omadacycline were superior to the rifampin-clarithromycin combination. The MuAL strain is useful in the rapid screening of drugs' efficacy and potency against M. ulcerans. We should leverage the progress made in the tuberculosis drug development pipeline to repurpose the drugs for the rapid development of new therapeutic modalities for Buruli ulcer.