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<p>Preferred therapies for NDM-producing <i>E. coli</i> include PBP3-targeting antibiotics. However, the global spread of amino acid insertions in PBP3 (PBP3i) among NDM-producing <i>E. coli</i> can compromise these antibiotics, causing near pan-β-lactam resistance. This study sought to determine if combinations targeting multiple PBPs provide enhanced activity against isolates with PBP3i. Clinical NDM-producing <i>E. coli</i> isolates with PBP3i (<i>n</i> = 3) or wild-type PBP3 (<i>n</i> = 1) underwent genomic and phenotypic characterization. PBP2 (zidebactam) and PBP3 inhibitors (aztreonam and cefepime), alone or in combination were evaluated. The activity of aztreonam/avibactam in time-kill assays correlated with each isolate’s MIC, regardless of PBP3 allele. Cefepime and zidebactam were synergistic against isolates with wild-type PBP3 but not PBP3i. In <i>E. coli</i> with PBP3i, zidebactam and cefepime/zidebactam produced similar killing profiles, indicating cefepime was minimally active. Accordingly, <i>E. coli</i> with PBP3i displayed morphological changes associated with PBP2 inhibition during cefepime/zidebactam treatment whereas isolates with wild-type PBP3 exhibited morphology characteristic of dual PBP2/PBP3 inhibition. Remarkably, aztreonam was synergistic with zidebactam in <i>E. coli</i> with PBP3i, producing eradication. In summary, cefepime/zidebactam synergistically inhibits PBP2 and PBP3 in isolates harboring wild-type PBP3 but predominantly PBP2 in the presence of PBP3i. Aztreonam and zidebactam engage PBP2 and mutant variants of PBP3, causing synergistic eradication of NDM-producing <i>E. coli</i> with PBP3i.</p>

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Near pan-β-lactam resistance in NDM-producing Escherichia coli with PBP3 insertions is overcome by dual PBP2/PBP3 inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Jackson V. Watkins,
  • Peter A. Smith,
  • Ryan T. Cirz,
  • Michael S. Lopez,
  • Nidhi Singh,
  • Keith E. Long,
  • Tengfei Long,
  • Liang Chen,
  • Zackery P. Bulman

摘要

Preferred therapies for NDM-producing E. coli include PBP3-targeting antibiotics. However, the global spread of amino acid insertions in PBP3 (PBP3i) among NDM-producing E. coli can compromise these antibiotics, causing near pan-β-lactam resistance. This study sought to determine if combinations targeting multiple PBPs provide enhanced activity against isolates with PBP3i. Clinical NDM-producing E. coli isolates with PBP3i (n = 3) or wild-type PBP3 (n = 1) underwent genomic and phenotypic characterization. PBP2 (zidebactam) and PBP3 inhibitors (aztreonam and cefepime), alone or in combination were evaluated. The activity of aztreonam/avibactam in time-kill assays correlated with each isolate’s MIC, regardless of PBP3 allele. Cefepime and zidebactam were synergistic against isolates with wild-type PBP3 but not PBP3i. In E. coli with PBP3i, zidebactam and cefepime/zidebactam produced similar killing profiles, indicating cefepime was minimally active. Accordingly, E. coli with PBP3i displayed morphological changes associated with PBP2 inhibition during cefepime/zidebactam treatment whereas isolates with wild-type PBP3 exhibited morphology characteristic of dual PBP2/PBP3 inhibition. Remarkably, aztreonam was synergistic with zidebactam in E. coli with PBP3i, producing eradication. In summary, cefepime/zidebactam synergistically inhibits PBP2 and PBP3 in isolates harboring wild-type PBP3 but predominantly PBP2 in the presence of PBP3i. Aztreonam and zidebactam engage PBP2 and mutant variants of PBP3, causing synergistic eradication of NDM-producing E. coli with PBP3i.