Études structurales et fonctionelles d'enzymes impliquées dans la voie de biosynthèse de la fidaxomicine, un antibiotique contre "Clostridium difficile"

Authors: Masselot--Joubert, Loreleï
Advisor: Shi, Rong
Abstract: Clostridium difficile is a bacterium that, with the depletion of gut flora during antibiotic treatment, produces two toxins that alter the intestinal wall causing potentially deadly diarrhea. The first treatments were based on vancomycin and resistance by C. difficile developed rapidly. In 2012, Health Canada approved a new antibiotic, fidaxomicin, which is also named tiacumicin B. This treatment is the most effective treatment against C. difficile. The macrocycle of tiacumicin B, a macrolactone, is produced by a soil bacterium and enzymes that act in the biosynthetic pathway are known. However, their order of action is not established. To know their order of action, it is necessary to know the substrates. This thesis presents the determination of TiaP1 structure, a cytochrome P450 that hydroxylates carbon 18 of the macrocycle of tiacumicin B. The structure of TiaP2, a P450 hydroxylating carbon 20, was already determined, and we attempted to predict its substrate by using a molecular docking approach. Our results confirm that TiaP2 hydroxylates before TiaP1. According to molecular docking results, we predict that the glycosyltransferase TiaG1 (not studied here) adds a sugar on the macrolactone of tiacumicin B before TiaP2 hydroxylates the carbon 20.
Document Type: Mémoire de maîtrise
Issue Date: 2016
Open Access Date: 24 April 2018
Permalink: http://hdl.handle.net/20.500.11794/28369
Grantor: Université Laval
Collection:Thèses et mémoires

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