Peptidoglycan Glycosyltransferase Substrate Mimics as Templates for the Design of New Antibacterial Drugs

Abstract

Peptidoglycan (PG) is an essential net-like macromolecule that surrounds bacteria, gives them their shape, and protects them against their own high osmotic pressure. PG synthesis inhibition leads to bacterial cell lysis, making it an important target for many antibiotics. The final two reactions in PG synthesis are performed by penicillin-binding proteins (PBPs). Their glycosyltransferase (GT) activity uses the lipid II precursor to synthesize glycan chains and their transpeptidase (TP) activity catalyzes the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death. β-lactam antibiotics target the transpeptidation reaction while antibiotic therapy based on inhibition of the GTs remains to be developed. Ongoing research is trying to fill this gap by studying the interactions of GTs with inhibitors and substrate mimics and utilizing the latter as templates for the design of new antibiotics. In this review we present an updated overview on the GTs and describe the structure-activity relationship of recently developed synthetic ligands.

Pseudomonas Aeruginosa : Targeting Cell-Wall Metabolism for New Antibacterial Discovery and Development

“…Perhaps the best-studied TG inhibitor is moenomycin A (Table 2); however, the therapeutic utility of this and related compounds is hampered by their poor pharmacokinetic properties [122]. Moreover, moenomycin-family antibiotics are generally ineffective against Gram-negatives due to their inability to cross the OM [123].…”

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

“…Polymerization of peptidyl disaccharide subunits is managed through the glycosyltransferase activity, and cross-linking by peptide bridges is catalyzed through the transpeptidase activity (Derouaux et al, 2013;Mesleh et al, 2016). Inhibition of the peptidoglycan synthesis was reported to result in bacterial cell lysis and subsequently death of the cell (Derouaux et al, 2013). Here, the metabolite-centric approach supported this phenomenon by predicting the related enzymes as the putative targets.…”

“…Penicillin-binding proteins (PBPs) carrying transpeptidase and/or glycosyltransferase activities are involved in the final stages of peptidoglycan synthesis. Polymerization of peptidyl disaccharide subunits is managed through the glycosyltransferase activity, and cross-linking by peptide bridges is catalyzed through the transpeptidase activity (Derouaux et al, 2013;Mesleh et al, 2016). Inhibition of the peptidoglycan synthesis was reported to result in bacterial cell lysis and subsequently death of the cell (Derouaux et al, 2013).…”

Peptidoglycan pathways: there are still more!

“…2, the nal step of PG biosynthesis is ultimately carried out by two enzymes: the peptidoglycan glycosyltransferase, which catalyzes lipid II polymerization to form a linear chain, and a transpeptidase. [16][17][18] Thus, lipid II units are a target of glycopeptide antibiotics like vancomycin, to pause further steps of polymerization. 16,19 As a result of the bacterial resistance that has developed against all these cell wall inhibitors, the need to target the glycosyltransferase (GT) has surfaced.…”