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

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

Author information

1
Swiss Tropical and Public Health Institute, Basel, 4051, Switzerland.
2
University of Basel, Basel, 4001, Switzerland.
3
Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore, 636921, Singapore.
4
CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Sorbonne Universités, UPMC Université Paris 06, Paris, 75005, France.
5
BASF SE, Ludwigshafen, 67063, Germany.
6
Red de Estudios Moleculares, AvanzadosInstituto de Ecología A. C., Xalapa, 91000, Veracruz, Mexico.
7
School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
8
Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, 189-0002, Japan.
9
Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, 173-8605, Japan.
10
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59715, USA.
11
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
12
CNR-MyRMA, Bactériologie Hygiène, Hôpitaux Universitaires Pitie Salpêtrière-Charles Foix, Paris, 75013, France.
13
Swiss Tropical and Public Health Institute, Basel, 4051, Switzerland. gerd.pluschke@swisstph.ch.
14
University of Basel, Basel, 4001, Switzerland. gerd.pluschke@swisstph.ch.
15
Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore, 636921, Singapore. kevin.pethe@ntu.edu.sg.
16
School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore. kevin.pethe@ntu.edu.sg.

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.

PMID:
30560872
PMCID:
PMC6299076
DOI:
10.1038/s41467-018-07804-8
[Indexed for MEDLINE]
Free PMC Article

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