Targeting the Mycobacterium ulcerans cytochrome bc 1:aa 3 for the treatment of Buruli ulcer

Nat Commun. 2018 Dec 18;9(1):5370. doi: 10.1038/s41467-018-07804-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa
  • Animals
  • Antibiotics, Antitubercular / pharmacology*
  • Antibiotics, Antitubercular / therapeutic use
  • Australia
  • Buruli Ulcer / drug therapy*
  • Buruli Ulcer / microbiology
  • Disease Models, Animal
  • Electron Transport Complex III / antagonists & inhibitors*
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / antagonists & inhibitors*
  • Electron Transport Complex IV / metabolism
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Inhibitory Concentration 50
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium ulcerans / drug effects*
  • Mycobacterium ulcerans / metabolism
  • Neglected Diseases / drug therapy*
  • Neglected Diseases / microbiology
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rifampin / pharmacology
  • Rifampin / therapeutic use
  • Treatment Outcome

Substances

  • Antibiotics, Antitubercular
  • Imidazoles
  • Piperidines
  • Pyridines
  • telacebec
  • Electron Transport Complex IV
  • Electron Transport Complex III
  • Rifampin