Buruli ulcer (BU) is a chronic necrotizing
skin disease caused by Mycobacterium ulcerans. Historically, the disease was treated by surgical excision of the skin lesions, until an 8-week combination
therapy of
rifampicin and
streptomycin was introduced in 2004. This treatment modality was effective and reduced recurrence rates.
Rifampicin is the most efficacious
antibiotic for the treatment of BU and, should
rifampicin-resistant M. ulcerans strains emerge, there is currently no replacement for it. As for mycobacterial diseases in general, there is a pressing need for the development of novel, fast-acting drugs. Under market economy conditions, repurposing of new
tuberculosis drug candidates is the most promising avenue for alternative BU treatments. Our
drug repurposing activities have led to the identification of several actives against M. ulcerans. In particular, the
cytochrome bc1 complex inhibitor
telacebec (
Q203) is a promising
drug candidate for the treatment of BU in Africa and Australia. While an active
cytochrome-bd
oxidase bypass limits the potency of the cytochrome-bc1-specific inhibitor
telacebec against M. tuberculosis, classical lineage M. ulcerans strains rely exclusively on cytochrome-bc1 to respire. Hence,
telacebec is effective at nanomolar concentration against M. ulcerans, and a high treatment efficacy in an experimental mouse
infection model indicates that treatment of BU could be substantially shortened and simplified by
telacebec.