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

Nicole Scherr, Raphael Bieri, Sangeeta S. Thomas, Aurélie Chauffour, Nitin Pal Kalia, Paul Schneide, Marie-Thérèse Ruf, Araceli Lamelas, Malathy S. S. Manimekalai, Gerhard Grüber, Norihisa Ishii, Koichi Suzuki, Marcel Tanner, Garrett C. Moraski, Marvin J. Miller, Matthias Witschel, Vincent Jarlier, Gerd Pluschke () and Kevin Pethe ()
Additional contact information
Nicole Scherr: Swiss Tropical and Public Health Institute
Raphael Bieri: Swiss Tropical and Public Health Institute
Sangeeta S. Thomas: Nanyang Technological University
Aurélie Chauffour: UPMC Université Paris 06
Nitin Pal Kalia: Nanyang Technological University
Paul Schneide: BASF SE
Marie-Thérèse Ruf: Swiss Tropical and Public Health Institute
Araceli Lamelas: Swiss Tropical and Public Health Institute
Malathy S. S. Manimekalai: Nanyang Technological University
Gerhard Grüber: Nanyang Technological University
Norihisa Ishii: National Institute of Infectious Diseases
Koichi Suzuki: National Institute of Infectious Diseases
Marcel Tanner: Swiss Tropical and Public Health Institute
Garrett C. Moraski: Montana State University
Marvin J. Miller: University of Notre Dame
Matthias Witschel: BASF SE
Vincent Jarlier: UPMC Université Paris 06
Gerd Pluschke: Swiss Tropical and Public Health Institute
Kevin Pethe: Nanyang Technological University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07804-8

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