Scholarlink

<p>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<sup>®</sup>) inhibitors of <i>E. coli</i> PBP3 (<i>Ec</i>PBP3) 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 <i>E. coli</i> 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 compounds bind to the transpeptidase active site cleft of PBP3 and represent, to our knowledge, a novel non-β-lactam chemical class of high affinity, non-covalent penicillin binding protein inhibitors. This work demonstrates an approach to rapidly find binders to antimicrobial targets, combined with an entry mechanism to provide access to the Gram negative cell.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月28日

查看全文
  • Catherine E. Rowland,
  • Hector Newman,
  • Tazmin T. Martin,
  • Rachel Dods,
  • Nikolaos Bournakas,
  • James M. Wagstaff,
  • Nick Lewis,
  • Steven J. Stanway,
  • Matthew Balmforth,
  • Celia Kessler,
  • Katerine van Rietschoten,
  • Dom Bellini,
  • David I. Roper,
  • Adrian J. Lloyd,
  • Christopher G. Dowson,
  • Michael J. Skynner,
  • Paul Beswick,
  • Michael J. Dawson

摘要

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 compounds bind to the transpeptidase active site cleft of PBP3 and represent, to our knowledge, a novel non-β-lactam chemical class of high affinity, non-covalent penicillin binding protein inhibitors. This work demonstrates an approach to rapidly find binders to antimicrobial targets, combined with an entry mechanism to provide access to the Gram negative cell.