Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

Abstract

Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc 1 :aa 3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidasedeficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3-and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 g/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIFϩSTR) and RPT and CFZ (RPTϩCFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIFϩSTR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

Q203 containing fully intermittent oral regimens exhibited high sterilizing activity against Mycobacterium ulcerans in mice

“…We therefore used a higher dose (1 mg/kg) that, still, failed to control infection in our model. Same unfavorable result was obtained with selamectine used at a dose of 12mg/kg as proposed in previous publication [19]. However, it has been suggested that these two avermectin compounds might be used safely at higher doses [12], which could be evaluated in future studies.…”

“…Triple combinations of Q203, administered at the higher dose of 10 mg/kg, either with RPT and clofazimine, RPT and BDQ or BDQ and clofazimine, as well as quadruple combination of these four drugs, were recently found to be sterilizing after 2 weeks of daily treatment in BU animal model [19], leading to the conclusion that targeting the M. ulcerans respiratory chain with several drugs is an efficient strategy for designing new shorter treatments of BU. In the present study, we demonstrated that double combinations of Q203 at 5 mg/kg with either RPT or BDQ, thanks to the long half-life and good bio availabilities of these drugs, provided very promising results for future fully oral intermittent regimens which would greatly simplify BU treatments in the field.…”

Telacebec for ultra-short treatment of Buruli ulcer in a mouse model

“…As an extremely potent inhibitor of M. ulcerans respiration, Q203 is an exceptional candidate for treatment-shortening regimens. Recently, we described 3-drug combinations of drugs active on the ETC with and without rifapentine that appeared capable of shortening the treatment of BU (16). Q203-containing regimens proved to be most effective and cured all mice after treatment for just 2 weeks.…”

“…However, unlike Mycobacterium tuberculosis , classical strains of M. ulcerans have a naturally occurring mutation in the cydA gene that renders the cytochrome bd oxidase non-functional (15). Therefore, most M. ulcerans strains causing BU are exquisitely susceptible to Q203 with very low MICs of 0.000075-0.00015 µg/ml (16, 17). In vivo studies also show Q203 to be a very attractive candidate for treatment of BU.…”

“…Scherr et al (17) showed that Q203 alone at a daily dose of just 0.5 mg/kg was as effective as RIF+STR and rendered 9/10 mice culture-negative with 8 weeks of treatment. Seeking a novel treatment-shortening regimen, we tested Q203 at 10 mg/kg/day in 3- and 4-drug combinations with high-dose RPT and other drugs acting on the ETC and oxidative phosphorylation (clofazimine (CFZ), and bedaquiline (BDQ)) and found that mouse footpads were sterilized after just 2 weeks of treatment (16).…”