Discovery and chemical optimisation of a potent, Bi-cyclic antimicrobial inhibitor of Escherichia coli PBP3.

ABSTRACT: Penicillin binding proteins (PBPs) are well validated antimicrobial targets, but the prevalence of β-lactamase driven resistance and, more rarely, target-based mutations, necessitates new classes of PBP-targeting drugs. Here we describe the discovery and optimisation of bicyclic peptide (Bicycle^®) inhibitors of E. coli PBP3 (EcPBP3) using a proprietary phage display platform, and their conjugation to linear antimicrobial peptides to confer outer membrane permeation. These molecules exhibited high-affinity binding to E. coli PBP3 and a viable spectrum of killing activity against clinically relevant species of the Enterobacterales. X-ray crystallography was used to explore the mode of binding to PBP3, enabling increased target affinity and improvement of in vitro stability. These

SUBMITTER: Rowland CE 

PROVIDER: S-EPMC12120022 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature