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<p>Gram-negative bacterial infections remain a critical global health challenge due to their complex membrane structure and limited treatment options. While peptide deformylase (PDF) inhibitors demonstrate potent activity against Gram-positive pathogens, their efficacy against Gram-negative species is constrained by poor outer membrane permeability. To address this, we rationally designed a novel series of ketone-incorporated compounds with enhanced structural rigidity to improve membrane penetration. Our lead compounds (<b>10a</b>, <b>10f</b>, <b>12b</b>) exhibited exceptional activity against <i>Acinetobacter baumannii</i> (MIC<sub>50</sub> &lt; 2&#xa0;μg/mL) and clinically isolated strains (MIC<sub>50</sub> &lt; 8&#xa0;μg/mL), with compound <b>6</b> showing particularly potent PDF inhibition (IC<sub>50</sub> = 70.8 ± 8.0&#xa0;nM). The lead compound demonstrated no significant cytotoxicity toward human hepatic stellate cells (LX-2) at the tested concentrations. Molecular docking confirmed their mechanism of action through competitive PDF binding. This work establishes a strategic framework for developing next-generation antibiotics against Gram-negative infections by optimizing membrane permeability while maintaining target inhibition.</p> Graphical abstract <p></p>

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Rational design of structurally rigidified ketone-peptide deformylase inhibitors with enhanced membrane permeability for combating gram-negative bacterial infections

  • 期刊论文

  • 发表日期：

    2025年4月22日

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  • Zhonghui Zhang,
  • Jidi Hu,
  • Maoqing Shi,
  • Xiaoxiao Gong,
  • Taoda Shi,
  • Hongxia Li,
  • Yu Qian,
  • Wenhao Hu

摘要

Gram-negative bacterial infections remain a critical global health challenge due to their complex membrane structure and limited treatment options. While peptide deformylase (PDF) inhibitors demonstrate potent activity against Gram-positive pathogens, their efficacy against Gram-negative species is constrained by poor outer membrane permeability. To address this, we rationally designed a novel series of ketone-incorporated compounds with enhanced structural rigidity to improve membrane penetration. Our lead compounds (10a, 10f, 12b) exhibited exceptional activity against Acinetobacter baumannii (MIC50 < 2 μg/mL) and clinically isolated strains (MIC50 < 8 μg/mL), with compound 6 showing particularly potent PDF inhibition (IC50 = 70.8 ± 8.0 nM). The lead compound demonstrated no significant cytotoxicity toward human hepatic stellate cells (LX-2) at the tested concentrations. Molecular docking confirmed their mechanism of action through competitive PDF binding. This work establishes a strategic framework for developing next-generation antibiotics against Gram-negative infections by optimizing membrane permeability while maintaining target inhibition.

Graphical abstract