title: Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis.
abstract: An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment.
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium. Electronic address: akoul@prdbe.jnj.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Najoua
authors.initials: N
authors.lastname: Dendouga
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: Balemans
authors.affiliation: Department of Functional Genomics, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Van den Wyngaert
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Vergauwen
authors.affiliation: Department of Functional Genomics, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Hinrich W H
authors.initials: HWH
authors.lastname: Göhlmann
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Willebrords
authors.affiliation: Pharmaceutical Research and Development, Tibotec NV, Johnson & Johnson, Campus de Maigremont-BP615, F-27106 Val de Reuil Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Poncelet
authors.affiliation: Pharmaceutical Research and Development, Tibotec NV, Johnson & Johnson, Campus de Maigremont-BP615, F-27106 Val de Reuil Cedex, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Guillemont
authors.affiliation: Department of Structural Biology, VU University Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
authors.affiliation: Department of Antimicrobial Research, B-2340 Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D000995:Antitubercular Agents / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D006706:Homeostasis; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry; D008954:Models, Biological; D009161:Mycobacterium / Q000378:metabolism*; D009163:Mycobacterium bovis / Q000187:drug effects / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D011804:Quinolines; D012333:RNA, Messenger; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases; D010100:Oxygen