Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer

Abstract

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a neglected tropical skin disease that is most commonly found in children from West and Central Africa. Despite the severity of the infection, therapeutic options are limited to antibiotics with severe side effects. Here, we show that M. ulcerans is susceptible to the anti-tubercular drug Q203 and related compounds targeting the respiratory cytochrome bc1:aa3. While the cytochrome bc1:aa3 is the primary terminal oxidase in Mycobacterium tuberculosis, the presence of an alternate bd-type terminal oxidase limits the bactericidal and sterilizing potency of Q203 against this bacterium. M. ulcerans strains found in Buruli ulcer patients from Africa and Australia lost all alternate terminal electron acceptors and rely exclusively on the cytochrome bc1:aa3 to respire. As a result, Q203 is bactericidal at low dose against M. ulcerans replicating in vitro and in mice, making the drug a promising candidate for Buruli ulcer treatment.

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

“…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. The dose of tedizolid TDZ used in the present study, 10 mg/kg, was shown to yield in mice pharmacokinetics close to that obtained in human at the therapeutic dose of 200mg [20-22].…”

“…The doses used in our experiment were drawn from available pharmacokinetic data. Ivermectine, a long lasting drug in human (half-life 15-19h) and in mice (9h) was shown when used in mice at a dose of 0.2mg/kg to yield serum concentration lower than that obtained in human at standard therapeutic dose [12]. We therefore used a higher dose (1 mg/kg) that, still, failed to control infection in our model.…”

“…Therefore, the excellent in vivo activity of Q203 against M. ulcerans constitutes a step forward. The reason of this promising result has been elucidated in a recent study: reductive evolution in most strains of this species led to hyper susceptibility to Q203 by eliminating alternate terminal electron acceptors and thus making the target cyt-bc1:aa3 crucial for survival [12].…”

“…As a first step, we screened several new drug candidates for their in vivo bactericidal activity against M. ulcerans . Based on available data on activity against M. tuberculosis or M. ulcerans , the following compounds, with either short or long half-life, were selected as potentially interesting: selamectin (SEL) and ivermectin (IVE), two drugs from the avermectin family with antiparasitic properties [4–6]; tedizolide (TDZ) [7], a new oxazolidinone sharing the same mechanism of action as linezolid (LZD), a drug active against M. ulcerans [8] but exhibiting higher solubility and bioavailability than LNZ [9]; the 2-piperazino-benzothiazinone 169 (PBTZ), shown to be highly active against M. tuberculosis [10,11]; the imidazopyridine amine Q203 that targets the cytochrome bc1-aa3 respiratory terminal oxidase in M. tuberculosis and recently shown to prevent mortality and reduce CFU counts in the footpad of mice infected with M. ulcerans [12].…”

Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

“…In contrast, M. ulcerans strains from Africa and Australia lack cytochrome bd and rely solely on the bc1-aa3 complex during respiration. Therefore, Q203 was found to be bactericidal against M. ulcerans (106). It is very possible that MAF L6 will be comparatively more susceptible to Q203 than MTB, given that the cytochrome bd rescue is also mutated in MAF L6.…”