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<p>Pyrrolobenzodiazepines (PBDs) containing C8-linked aliphatic heterocycles have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant Gram-negative pathogens, including <i>Klebsiella pneumoniae</i>. When isolates were exposed to PBDs, they acquired resistance, with significant increases in inhibitory concentrations. Resistant strains showed mutations in genes associated with resistance to albicidin, specifically <i>tsx</i> and <i>merR</i>-family regulator <i>albA</i>. Heterologous expression of AlbA in <i>E. coli</i> and introducing the L120Q AlbA resistance-mediating modification into the genome of a sensitive <i>K. pneumoniae</i> strain conferred PBD and albicidin resistance. Proteomic analysis of the resistant strains showed elevated AlbA protein levels compared to isogenic wild-type strains. Crystallographic studies with the antibiotic binding domain of AlbA show binding of KMR-14-14 to the same groove shown to bind albicidin. Given the parallels between these two structurally unrelated compound classes, AlbA may offer resistance to further antibiotics and should be considered in future antibiotic discovery.</p>

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Convergent evolution of antibiotic resistance mechanisms between pyrrolobenzodiazepines and albicidin in multidrug resistant Klebsiella pneumoniae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月6日

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  • Yasmin M. Surani,
  • Matthew E. Wand,
  • Pietro Picconi,
  • Michele Di Palma,
  • Riccardo Zenezini Chiozzi,
  • Md. Mahbub Hasan,
  • Paolo Andriollo,
  • Stefan Grätz,
  • Kazi S. Nahar,
  • Michael Maynard-Smith,
  • Roderich D. Süssmuth,
  • Roberto A. Steiner,
  • Khondaker Miraz Rahman,
  • Charlotte K. Hind,
  • J. Mark Sutton

摘要

Pyrrolobenzodiazepines (PBDs) containing C8-linked aliphatic heterocycles have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant Gram-negative pathogens, including Klebsiella pneumoniae. When isolates were exposed to PBDs, they acquired resistance, with significant increases in inhibitory concentrations. Resistant strains showed mutations in genes associated with resistance to albicidin, specifically tsx and merR-family regulator albA. Heterologous expression of AlbA in E. coli and introducing the L120Q AlbA resistance-mediating modification into the genome of a sensitive K. pneumoniae strain conferred PBD and albicidin resistance. Proteomic analysis of the resistant strains showed elevated AlbA protein levels compared to isogenic wild-type strains. Crystallographic studies with the antibiotic binding domain of AlbA show binding of KMR-14-14 to the same groove shown to bind albicidin. Given the parallels between these two structurally unrelated compound classes, AlbA may offer resistance to further antibiotics and should be considered in future antibiotic discovery.