GlcNAc-1,6-anhydro-MurNAc Moiety Affords Unusual Glycosyl Acceptor that Terminates Peptidoglycan Elongation

• DOI: 10.1021/jacs.3c12526
• Publication Date: 2024-03-08T15:04:06Z
• Authors: Xiao-Lin Zhang; Gábor Báti; Chenyu Li; Aoxin Guo; Claresta Yeo; Han Ding; Kumar Bhaskar Pal; Yuan Xu; Yuan Qiao; Xue-Wei Liu
• Keywords: Glycosyl donor; Lipid II; Moiety; Depsipeptide

Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple incoming glycosyl acceptor to donor. Interfering with TGase activity can interrupt assembly. Existing inhibitors like moenomycin and Lipid II analogues always occupy active sites; other strategies interfere proper elongation have not been widely exploited. Inspired by natural 1,6-anhydro-MurNAc termini that mark ends strands we hypothesized incorporation anhydromuramyl-containing into growing may effectively inhibit elongation. To explore this possibility, synthesized 4-O-(N-acetyl-β-d-glucosaminyl)-1,6-anhydro-N-acetyl-β-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, demonstrated anhydromuropeptide its analogue lacking peptide, 1-deAA, were both utilized as noncanonical anhydro acceptors vitro. The anhydromuramyl moiety TGases afforded efficient termination glycan chain extension. Moreover, preliminary vitro studies 1-deAA against Staphylococcus aureus showed served reasonable antimicrobial adjunct vancomycin. These insights imply potential application such anhydromuropeptides novel classes PG-terminating inhibitors, pointing toward antibacterial agent development.