Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity

Citations Over TimeTop 15% of 2015 papers

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.

Related Papers

• → Class A PBPs have a distinct and unique role in the construction of the pneumococcal cell wall(2020)66 cited
• → Synthesis of Heptaprenyl−Lipid IV to Analyze Peptidoglycan Glycosyltransferases(2007)77 cited
• → Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity(2015)33 cited
• → Bifunctional Penicillin-Binding Proteins: Focus on the Glycosyltransferase Domain and its Specific Inhibitor Moenomycin(2002)22 cited
• → Continuous Fluorescence Assay for Peptidoglycan Glycosyltransferases(2016)10 cited