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Caractérisation génétique, biochimique et structurale de l'ATP synthase des mycobactéries, la cible d'un nouvel antituberculeux de la famille des diarylquinolines

Abstract : TMC207 is a new antituberculous drug, which inhibits very efficiently the ATP synthase of mycobacteria such as M. 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, D28G, D28A, L59V, E61D, A63P and I66M, have been identified in the subunit c forming a c-ring in the ATP synthase. They were studied by evaluating the levels of resistance they confer in the selected clones and in M. smegmatis by using an isogenic complementation system. The rates of increase of TMC207 MIC values were interpreted by constructing by homology modeling a structure of the 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, define a cleft located between two adjacent c subunits in the c-ring. This cleft, which encompasses the proton binding site, is well fitted to bind TMC207 at the level of the bromo-quinoline moiety, the drug being anchored by several bonds. Finally, we have expressed and purified the mycobacterial ATP synthase in order to begin the structural study of this enzyme by electron microscopy and x-ray diffraction. Our results of electron microscopy allow obtaining the first images of the ATP synthase of M. smegmatis
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Submitted on : Friday, June 21, 2013 - 9:41:44 AM
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  • HAL Id : tel-00836521, version 1

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Elena Segala. Caractérisation génétique, biochimique et structurale de l'ATP synthase des mycobactéries, la cible d'un nouvel antituberculeux de la famille des diarylquinolines. Microbiologie et Parasitologie. Université Pierre et Marie Curie - Paris VI, 2012. Français. ⟨NNT : 2012PA066057⟩. ⟨tel-00836521⟩

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