Toward a single dose cure for Buruli ulcer

Abstract

25A single dose of TELACEBEC (Q203), a phase 2 clinical candidate for tuberculosis, eradicates 26 Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 27 weeks post treatment. Clinical use of Q203 could dramatically simplify the clinical management 28 of Buruli ulcer, a neglected mycobacterial disease. 29 Text 30 Buruli ulcer is a chronic ulcerating disease of the skin and underlying tissues caused by 31 Mycobacterium ulcerans. The disease is regaining importance in West Africa and South East 32Australia with increasing incidence and severity (1, 2). The current treatment strategy involves 33 an eight-week regimen of rifampicin administered with streptomycin or clarithromycin (3, 4). 34Disease management is complicated by an underreporting, especially in rural Africa (5), social 35 stigmata, and lack of awareness that impede the deployment of medical treatment. Inadequate 36 therapy may drive a substantial number of permanent disabilities, especially in children. 37Compliance to an eight-week therapy is also a serious limitation. 38Telacebec (Q203) is an imidazopyridine amide drug targeting the mycobacterial cytochrome 39 bcc:aa 3 terminal oxidase. The drug candidate, currently in clinical trial phase 2 for tuberculosis 40 (6), has excellent activity against M. ulcerans in vitro and in vivo (7)(8)(9). In Mycobacterium 41 3 tuberculosis, the bactericidal potency of Q203 is limited by the presence of the cytochrome bd 42 oxidase, an alternate terminal oxidase. The exquisite sensitivity of M. ulcerans to Q203 is 43 explained by the absence of a functional cytochrome bd oxidase in this species (10, 11). 44Considering the distinct potency of Q203 coupled with a long half-life and favourable 45 toxicological profile (7, 10), we evaluated the potency of a single dose of Q203 to eradicate M. 46 ulcerans in an established mouse model of Buruli ulcer infection. BALB/c mice were infected in 47 97

Mycobacterial skin infection

“…Among new drugs, telacebec is promising in terms of potency, shorter duration (2 weeks) and tolerability in animal studies [64,[81][82][83]. In January 2021, telacebec was recognized as an orphan drug by US Food and Drug Administration.…”

Suffocating tuberculosis : oxidative phosphorylation as a target space for the development of next generation anti-tuberculosis drugs

“…Drug susceptibility testing against strains of the classical lineage showed hypersensitivity to Q203, with a minimum inhibitory concentration (MIC) value 10 times lower than that in M. tuberculosis (133). Additionally, Q203 was bactericidal against M. ulcerans both in vitro and in vivo (133,134). Importantly, Q203 demonstrated no sterilising effect against the ancestral lineage of M.…”

“…In the context of the respiratory terminal oxidases in M. tuberculosis, combining chemical inhibition with genetic studies have clearly demonstrated the synthetic lethal relationship between the two terminal oxidases: Cyt-bcc:aa3 and Cyt-bd (75). The striking potency exhibited by Q203 (Telacebec) against M. ulcerans served as a precedent that the synthetic lethality of the two complexes could be exploited in M. tuberculosis (133,134). Given the abundance of antibacterials targeting Cyt-bcc:aa3, finding a small molecule inhibitor targeting Cyt-bd could improve the sterilising potency of many antibiotics against M. tuberculosis.…”

Evaluating the attractiveness of the terminal oxidases as drug targets in mycobacterium abscessus

“…Q203 has also shown excellent potency against the NTM Mycobacterium ulcerans, the etiological agent of Buruli ulcer and is now considered a promising drug for the treatment of the disease (201,211).…”