Authors
Dmytro Voskoboinyk, Martin E Tanner
Published in
Chemistry (Weinheim an der Bergstrasse, Germany). Pages e71774. Oct 06, 2026. Epub Oct 06, 2026.
Abstract
Peptidoglycan (PG) is the key structural component of the bacterial cell wall, responsible for cellular shape and structural integrity. Postsynthetic modifications to PG enable bacteria to evade innate immunity and regulate endogenous autolysins. Among these, C-6 O-acetylation protects PG from lysozyme degradation, while O-acetylpeptidoglycan esterase (Ape) removes this modification to restore the free C-6 hydroxyl group required for lytic transglycosylase activity. Deletion of the ape gene resulted in aberrant cell morphology and attenuated virulence, identifying Ape as a potential antibacterial target. Previously, we reported aldehyde-based competitive inhibitors (Ki = 13 µM) of Ape from Campylobacter jejuni and demonstrated that formation of a covalent hemiacetal adduct, which mimics the tetrahedral intermediate in catalysis, is critical for binding. In this work, we expanded the inhibitor series to examine the contributions of the peptide stem, the anomeric substituent, and the electrophilic carbonyl functionality to Ape inhibition. The synthesized reversible competitive inhibitors exhibited micromolar to submillimolar potency. Peptide stem extension provided little improvement in affinity, while a benzyl substituent at the anomeric position reduced inhibitory potency. Monofluorinated analogues showed modest improvements, whereas difluoroaldehyde and trifluoromethyl ketone derivatives displayed reduced affinity. Finally, irreversible covalent inhibitors bearing dimethylphosphonate and epoxide functionalities proved ineffective against Ape.
PMID:
42839612
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
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