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<p>The rising incidence of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) poses a significant threat to global public health, highlighting the urgent need for novel therapies and treatments in clinical settings. Caseinolytic protease P (ClpP) serves as a key component of bacterial degradation systems, playing a crucial role in maintaining cellular homeostasis and contributing to pathogenicity. Targeting ClpP function inhibition has demonstrated potential in combating antibiotic resistance and offers a promising therapeutic strategy for treating <i>S. aureus</i> infections. In this study, coniferaldehyde (CA) was identified as a ClpP inhibitor through ClpP peptidase inhibition assay. CA reduced the hemolysis activity, protease hydrolysis and bacterial invasion ability via regulating the transcription of main virulence factors. Furthermore, CA treatment led to a decreased resistance of <i>S. aureus</i> to adverse stimuli, including heat, acidic pH, high osmotic environment, hydrogen peroxide and NaClO stress assays. Notably, CA enhanced the efficacy of the bactericidal antibiotic tigecycline against growing <i>S. aureus</i> in time-killing assays. Molecular simulations and mutagenesis analyses revealed that the amino acids M31 and G33 were critical for the interaction between CA and ClpP. Importantly, CA exhibited excellent protective efficacy against <i>S. aureus</i> pneumonia in murine infection models. Our findings confirm that CA is an effective ClpP inhibitor with potential as a therapeutic agent for <i>S. aureus</i> infections.</p> Graphical Abstract <p></p>

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Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月30日

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  • Shufang Li,
  • Yan Zhang,
  • Jianfeng Wang,
  • Hongfa Lv,
  • Hongxia Ma,
  • Lingcong Kong,
  • Yonglin Zhou,
  • Jingmin Gu,
  • Wei Li,
  • Qiaoling Zhang

摘要

The rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health, highlighting the urgent need for novel therapies and treatments in clinical settings. Caseinolytic protease P (ClpP) serves as a key component of bacterial degradation systems, playing a crucial role in maintaining cellular homeostasis and contributing to pathogenicity. Targeting ClpP function inhibition has demonstrated potential in combating antibiotic resistance and offers a promising therapeutic strategy for treating S. aureus infections. In this study, coniferaldehyde (CA) was identified as a ClpP inhibitor through ClpP peptidase inhibition assay. CA reduced the hemolysis activity, protease hydrolysis and bacterial invasion ability via regulating the transcription of main virulence factors. Furthermore, CA treatment led to a decreased resistance of S. aureus to adverse stimuli, including heat, acidic pH, high osmotic environment, hydrogen peroxide and NaClO stress assays. Notably, CA enhanced the efficacy of the bactericidal antibiotic tigecycline against growing S. aureus in time-killing assays. Molecular simulations and mutagenesis analyses revealed that the amino acids M31 and G33 were critical for the interaction between CA and ClpP. Importantly, CA exhibited excellent protective efficacy against S. aureus pneumonia in murine infection models. Our findings confirm that CA is an effective ClpP inhibitor with potential as a therapeutic agent for S. aureus infections.

Graphical Abstract