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<p>Antimicrobial peptides (AMPs) exhibit diverse antibacterial mechanisms. To elucidate the intracellular targets of the novel AMP, EWAMP-R, we generate EWAMP-R-resistant strains of <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>. In <i>E. coli</i>, a nonsynonymous mutation in the <i>clpX</i> gene (1108 C &gt; T) is identified, resulting in an amino acid change in ClpX (R370C). This mutation confers enhanced tolerance to EWAMP-R and induces a “hyperflagellate phenotype” in EWAMP-R-resistant <i>E. coli</i>, as verified by CRISPR/Cas9-generated <i>clpX</i> (1108 C &gt; T) mutants. Further studies reveal that EWAMP-R can bind to the Walker A motif and inhibit the conformational changes of ClpX, suppressing its ATPase activity and the degradation of its substrates, such as LexA 1-84. The accumulation of LexA 1-84 downregulates the SOS response, inducing apoptosis-like death in <i>E. coli</i>. In contrast, EWAMP-R-resistant <i>S. aureus</i> exhibits only a metabolic slowdown. These findings establish ClpX as a novel target for AMPs and highlight EWAMP-R as a promising antibacterial agent.</p>

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Identification of intracellular target of antimicrobial peptide EWAMP-R in bacteria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Yizhao Wu,
  • Hao Tang,
  • Puguo Hao,
  • Yunxiang Xu,
  • Yifan Zhang,
  • Muyuan Wang,
  • Rui Jiang,
  • Jibao Jiang,
  • Qi Zhao,
  • Yinsheng Li

摘要

Antimicrobial peptides (AMPs) exhibit diverse antibacterial mechanisms. To elucidate the intracellular targets of the novel AMP, EWAMP-R, we generate EWAMP-R-resistant strains of Escherichia coli and Staphylococcus aureus. In E. coli, a nonsynonymous mutation in the clpX gene (1108 C > T) is identified, resulting in an amino acid change in ClpX (R370C). This mutation confers enhanced tolerance to EWAMP-R and induces a “hyperflagellate phenotype” in EWAMP-R-resistant E. coli, as verified by CRISPR/Cas9-generated clpX (1108 C > T) mutants. Further studies reveal that EWAMP-R can bind to the Walker A motif and inhibit the conformational changes of ClpX, suppressing its ATPase activity and the degradation of its substrates, such as LexA 1-84. The accumulation of LexA 1-84 downregulates the SOS response, inducing apoptosis-like death in E. coli. In contrast, EWAMP-R-resistant S. aureus exhibits only a metabolic slowdown. These findings establish ClpX as a novel target for AMPs and highlight EWAMP-R as a promising antibacterial agent.