Défense de thèse de doctorat en sciences chimiques - Huixiao Fu

Discovery of inhibitors of the bacterial lipopolysaccharide as anti-virulence agents

Jury

Moreno GALLENI (Ulg), Caroline STEVIGNY (ULB), Weidong PAN (Key laboratory of chemistry for natural products of Guizhou province and chinese academy of sciences), Xavier DE BOLLE, président (UNamur), Stéphane VINCENT, promoteur (UNamur)

Résumé

Lipopolysaccharide (LPS) is a glycolipid pivotal virulence factor of Gram-negative bacteria. Its inhibition at the oligosaccharide core level generate bacteria with a truncated LPS that are much less virulent and more sensitive towards antibiotics. Thus, the inhibition of bacterial heptose, which is the first sugar unit that link Kdo₂-lipid A moiety and core oligosaccharide, represents an attractive target to discover anti-virulence agents. Novel inhibitors of the enzymes that are involved in the biosynthesis of ADP-heptose, the precursor of LPS heptose, are the main topic of this thesis.

In this thesis, we mainly focused on the understanding of heptosyltransferase (WaaC) catalytic mechanism and the identification of novel WaaC inhibitors. Several series of compounds, such as heavily fluorinated heptoside, multivalent glycoclusters, ADP-heptose analogues, natural products and drug-like molecules were screened against WaaC. The inhibitory activity assay of the best WaaC inhibitors against LPS biosynthesis was performed by a new developed whole cell assay on Yersinia enterocolitica O:9 via labeling the oligosaccharide with a specific antibody.

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