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<p>It is now well-established that <i>Staphylococcus aureus</i> can produce a range of toxin proteins, resulting in a spectrum of pathological conditions when it infects individuals with pre-existing medical conditions or immunocompromised. Among these, MRSA is one of the most prominent antimicrobial-resistant organisms and a significant cause of mortality in many patients. It has been demonstrated that <i>Staphylococcus aureus</i> lipase (SAL) is a vital factor in the proliferation of this bacterium. A combination of <i>in silico </i>screening and X-ray crystallography was employed to analyze inhibitors of SAL, and the results were highly significant. <i>In silico</i> screening identified a number of compounds, and the enzyme activity assay demonstrated that the antipsychotic drug penfluridol exhibited potent inhibitory activity against SAL. We have conducted co-crystallization of penfluridol and SAL on the ground and in space. The resulting co-crystals were subjected to data measurement using the synchrotron radiation facility at SPring-8, and the complex structure was determined. The crystal structure of the penfluridol-SAL complex was determined at 2.2&#xa0;Å resolution, thereby providing the structural basis for developing new anti-infective agents that inhibit the growth of <i>Staphylococcus aureus</i>. These findings are anticipated to facilitate the development of compounds with potent inhibitory activity.</p>

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Structural analysis shows the mode of inhibition for Staphylococcus aureus lipase by antipsychotic penfluridol

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • Julia Kitadokoro,
  • Takatsugu Hirokawa,
  • Masayuki Kamo,
  • Naoki Furubayashi,
  • Yukiko Okuno,
  • Takaaki Hikima,
  • Masaki Yamamoto,
  • Koji Inaka,
  • Katsumi Maenaka,
  • Shigeki Kamitani,
  • Kengo Kitadokoro

摘要

It is now well-established that Staphylococcus aureus can produce a range of toxin proteins, resulting in a spectrum of pathological conditions when it infects individuals with pre-existing medical conditions or immunocompromised. Among these, MRSA is one of the most prominent antimicrobial-resistant organisms and a significant cause of mortality in many patients. It has been demonstrated that Staphylococcus aureus lipase (SAL) is a vital factor in the proliferation of this bacterium. A combination of in silico screening and X-ray crystallography was employed to analyze inhibitors of SAL, and the results were highly significant. In silico screening identified a number of compounds, and the enzyme activity assay demonstrated that the antipsychotic drug penfluridol exhibited potent inhibitory activity against SAL. We have conducted co-crystallization of penfluridol and SAL on the ground and in space. The resulting co-crystals were subjected to data measurement using the synchrotron radiation facility at SPring-8, and the complex structure was determined. The crystal structure of the penfluridol-SAL complex was determined at 2.2 Å resolution, thereby providing the structural basis for developing new anti-infective agents that inhibit the growth of Staphylococcus aureus. These findings are anticipated to facilitate the development of compounds with potent inhibitory activity.