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Synthèse de bisubstrats et biligands pour la conception d’inhibiteurs inédits de la désoxyxylulose phosphate réducto-isomérase (DXR) : nouveaux antimicrobiens

Abstract : The development of new antimicrobial is a necessity due to the emergence of multidrug resistance. Isoprenoids are a key target as they play an essential role in the maintenance of proper functions in all living organisms. Isoprenoids derive from two precursors: IPP and DMAPP, synthesized via the MVA or MEP pathway. The last one, absent in human but present in many pathogenic bacteria, all the enzymes of the MEP pathway therefore represent efficient targets, as the desoxyxylulose phosphate reductoisomerase (DXR). Owing the rapid emergence of resistance toward fosmidomycine, an efficient inhibitor of DXR, we synthesized analogues of this anitbiotic, appropriately functionalized to target the NADPH binding site or an allosteric pocket, as well as the DXP, the natural substrate of DXR. By targeting both sites, we should improve the affinity and efficiency of the inhibitors. The biligand and bisubstrate approaches, have been implemented. The compounds have shown interesting results, with IC50 in the low micro-molar. Notably, one inhibitor has shown comparable results to the fosmidomycine with an IC50 at nanomolar level.
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Aurore Dreneau. Synthèse de bisubstrats et biligands pour la conception d’inhibiteurs inédits de la désoxyxylulose phosphate réducto-isomérase (DXR) : nouveaux antimicrobiens. Autre. Université de Strasbourg, 2017. Français. ⟨NNT : 2017STRAF037⟩. ⟨tel-02945693⟩

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