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Metabolic inhibitors of bacterial glycan biosynthesis

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Abstract

The bacterial cell wall is a quintessential drug target due to its critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell wall glycocalyx contains distinctive monosaccharides that are absent from human cells, and proper assembly of monosaccharides into higher-order glycans is critical for bacterial fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare deoxy amino sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the creation of glycosylation inhibitors. To ease the study of bacterial glycan function in the absence of detailed structural or enzyme information, we crafted metabolic inhibitors based on rare bacterial monosaccharide scaffolds. Metabolic inhibitors were assessed for their ability to interfere with glycan biosynthesis and fitness in pathogenic and symbiotic bacterial species. Three metabolic inhibitors led to dramatic structural and functional defects in Helicobacter pylori. Strikingly, these inhibitors acted in a bacteria-selective manner. These metabolic inhibitors will provide a platform for systematic study of bacterial glycosylation enzymes not currently possible with existing tools. Moreover, their selectivity will provide a pathway for the development of novel, narrow-spectrum antibiotics to treat infectious disease. Our inhibition approach is general and will expedite the identification of bacterial glycan biosynthesis inhibitors in a range of systems, expanding the glycochemistry toolkit.

Graphical abstract: Metabolic inhibitors of bacterial glycan biosynthesis

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Article information


Submitted
25 Nov 2019
Accepted
08 Jan 2020
First published
08 Jan 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Metabolic inhibitors of bacterial glycan biosynthesis

D. A. Williams, K. Pradhan, A. Paul, I. R. Olin, O. T. Tuck, K. D. Moulton, S. S. Kulkarni and D. H. Dube, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC05955E

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