Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity
Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide–peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross‐linking by penicillin‐binding proteins and is essential for growth for key bac...
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Published in | Chemical biology & drug design Vol. 87; no. 2; pp. 190 - 199 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Blackwell Publishing Ltd
01.02.2016
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Subjects | |
Online Access | Get full text |
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Summary: | Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide–peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross‐linking by penicillin‐binding proteins and is essential for growth for key bacterial pathogens. As such, bacterial cell wall glycosyltransferases are an attractive target for antibiotic drug discovery. However, significant challenges to the development of inhibitors for these targets include the development of suitable assays and chemical matter that is suited to the nature of the binding site. We developed glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. In addition, we designed a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug‐like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bound and inhibited the glycosyltransferase enzymes, and these compounds could serve as chemical entry points for antibiotic development.
Cell wall biogenesis for many clinically‐relevant bacterial pathogens requires the activity of peptidoglycan glycosyltransferases. We report the synthesis of disaccharide‐like compounds based on the peptidoglycan glycosyltransferase inhibitor moenomycin. We show, using a newly developed functional assay and NMR binding studies, that a subset of these compounds bind and inhibit peptidoglycan glycosyltransferase enzymes as expected. |
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Bibliography: | Nicholas Beauchemin at Cubist Pharmaceuticals istex:DD7081D5C0A94231462C2012BF979B2CFB8517B3 ark:/67375/WNG-M7KF01X8-Q ArticleID:CBDD12662 Christopher Dowson and David Roper at University of Warwick Daniel C. Bensen formerly from Trius Therapeutics BACWAN (Bacterial Cell Wall Associated Network) Kien Nguyen, Aileen Rubio, Dominic Ryan, and Jared Silverman at Cubist Pharmaceuticals ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1747-0277 1747-0285 |
DOI: | 10.1111/cbdd.12662 |