Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity. (9th October 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Chemical biology & drug design. Volume 87:Number 2(2016)
• Page Start: 190
• Page End: 199
• Publication Date: 2015-10-09
• Subjects: drug discovery -- glycosyltransferase -- NMR spectroscopy -- penicillin‐binding protein -- transglycosylase; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12662
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : 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. Abstract : 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.