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Antimicrob Agents Chemother. 2012 May;56(5):2326-34. doi: 10.1128/AAC.06154-11. Epub 2012 Feb 21.

New mutations in the mycobacterial ATP synthase: new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure.

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1
Laboratoire de Bactériologie-Hygiène, ER5 EA1541, UPMC Université Paris 06, Faculté de Médecine Pitié-Salpêtrière, Paris, France.

Abstract

TMC207 is a new antituberculous drug belonging to the diarylquinoline class which very efficiently inhibits the ATP synthase of mycobacteria such as Mycobacterium tuberculosis, one of the most important pathogens in the world. In order to map the amino acid residues involved in the binding of the drug, we have selected in vitro TMC207-resistant mutants from M. tuberculosis and diverse atypical mycobacteria. Six distinct mutations, Asp28 → Gly, Asp28 → Ala, Leu59 → Val, Glu61 → Asp, Ala63 → Pro, and Ile66 → Met, have been identified in the subunit c forming a C ring in the ATP synthase. They were studied by evaluating the levels of resistance that they confer in the selected clones and by using an isogenic complementation system in Mycobacterium smegmatis. The rates of increase of TMC207 MIC values (8- to 133-fold) were interpreted by constructing by homology modeling a structure of the mycobacterial C ring which was used for docking simulations with TMC207. Our results suggest that the residues found to be mutated in the resistant clones, together with a tyrosine specifically conserved at position 64 in mycobacteria, define a cleft located between two adjacent c subunits in the C ring. This cleft, which encompasses the proton-binding site (Glu61), is well fitted to bind TMC207 at the level of the bromoquinoline moiety, with the drug being anchored by several ionic, hydrogen, and halogen bonds with residues Glu61, Tyr64, and Asp28, respectively. These data shed light on the molecular interactions allowing TMC207 to bind specifically and efficiently at the level of the proton-binding site of the mycobacterial C ring.

PMID:
22354303
PMCID:
PMC3346594
DOI:
10.1128/AAC.06154-11
[Indexed for MEDLINE]
Free PMC Article
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