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Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity
Author(s) -
Mesleh Michael F.,
Rajaratnam Premraj,
Conrad Mary,
Chandrasekaran Vasu,
Liu Christopher M.,
Pandya Bhaumik A.,
Hwang You Seok,
Rye Peter T.,
Muldoon Craig,
Becker Bernd,
Zuegg Johannes,
Meutermans Wim,
Moy Terence I.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12662
Subject(s) - lipid ii , glycosyltransferase , peptidoglycan , glycan , disaccharide , biochemistry , penicillin binding proteins , cell wall , bacterial cell structure , enzyme , chemistry , biology , bacteria , escherichia coli , glycoprotein , gene , genetics
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.