Effect of the lipid II sugar moiety on bacterial transglycosylase: the 4-hydroxy epimer of lipid II is a TGase inhibitor

Abstract

Lipid II analogues bearing major modifications on the second sugar (GlcNAc) were synthesized and evaluated for their substrate activity toward TGases. Unexpectedly, N-deacetyled lipid II decreased its activity dramatically, and the C4-axial OH lipid II became an inhibitor (IC = 8 μM) with an approximately 14-fold increase in binding affinity toward TGase (25 vs. 27).

Targeting the Bacterial Transglycosylase: Antibiotic Development from a Structural Perspective

“…For the saccharide moiety of lipid II, Shih et al found that lipid II analogs with a longer sugar chain led to an increased affinity with TG; 49 since lipid II can bind to either the acceptor or the donor site, an elongated sugar chain should have stronger binding at the donor site. It was also found that the Ndeacetylation of the GlcNAc of lipid II analogs led to a notable decrease in inhibition activities, 75 in agreement with the structural observation that the N-acetyl methyl group of the moenomycin sugar ring E interacts with the conserved hydrophobic patch at the donor site (Figure 3a).…”

“…In the early years, lipid II analogs received much less attention than moenomycin, partly because they have much weaker potency compared to moenomycin analogs and, most importantly, they are much more difficult to obtain either enzymatically or synthetically. − In the 2010s, with advanced methods for lipid II synthesis being developed ,, and the first structure of a lipid II-analog-bound TG being solved, there was a revived interest in the field of lipid II analogs. This structure not only revealed a detailed acceptor–site interface but also provided a structural explanation of how the epimerization of the C4–OH group from GlcNAc to GalNAc in lipid II converted it from a substrate into an inhibitor . During that time, chemical modifications on different moieties of lipid II were extensively explored to obtain a better understanding of this molecule as a potential TG inhibitor.…”

“…This structure not only revealed a detailed acceptor− site interface but also provided a structural explanation of how the epimerization of the C4−OH group from GlcNAc to GalNAc in lipid II converted it from a substrate into an inhibitor. 75 During that time, chemical modifications on different moieties of lipid II were extensively explored to obtain a better understanding of this molecule as a potential TG inhibitor.…”

Recent Advances in the Synthesis and Biological Applications of Peptidoglycan Fragments

“…Several derivatives of Lipid II were made wherein the GlcNAc sugar was replaced by 6‐azido‐GlcNAc 118 , 3‐deoxyGlcNAc 119 , GalNAc 120 , or unmodified 2‐ N ‐glucosamine 121 (Figure 14). [150] These inhibitors all possessed fluorescently labelled phospholipid tails and simple alanine stem peptides. The azido‐derivative was an excellent substrate for transglycosylase, whereas the 3‐deoxy and free amine derivatives were not.…”

Simultaneously and separately immobilizing incompatible dual-enzymes on polymer substrate via visible light induced graft polymerization

“…TGase is one enzyme which can incorporate chemicals containing primary amines (e.g. lysine) into the protein 6 substrate which contains γ-glutaminyl residues [34][35]. Trypsin is one specific digestive enzyme which can cut arginine or lysine on the carboxyl end of proteins or peptides [36][37][38].…”