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<p>The limitations of existing drugs and the development of drug resistance make it urgent to develop new drugs against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The re-development of the antibacterial activity of drugs that have already been proven safe for human use is an effective way. In this study, we discovered that the Src homology region 2 domain-containing phosphatase-1 (SHP-1) agonist SC-43, exhibits potent activity against Gram-positive bacteria, including MRSA. The mode of action studies revealed that SC-43 inhibits the key enzyme coproporphyrin ferrochelatase (CpfC) of the coproporphyrin-dependent (CPD) heme synthesis pathway and interferes with the bacterial porphyrin metabolism. The determination of the structure of CpfC derived from <i>S. aureus</i> (SA<sub>CpfC</sub>) in this study allowed us to reveal the inhibitory effect of SC-43 at the molecular level. Animal experiments showed that SC-43 has the potential to become a new anti-MRSA drug. In conclusion, this study discovered a new anti-MRSA activity of a drug currently undergoing clinical trials and simultaneously verified the feasibility of developing new anti-Gram-positive bacteria drugs by inhibiting the CPD pathway.</p>

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SHP-1 agonist SC-43 limits methicillin-resistant Staphylococcus aureus infection through inhibition of heme biosynthesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Yini Huang,
  • Yan Ye,
  • Xinmei Zhu,
  • Dengpan Liang,
  • Ruiqin Cui,
  • Xiaopeng Yuan,
  • Xitao Li,
  • Quanming Zou,
  • Haibo Li,
  • Wei Huang

摘要

The limitations of existing drugs and the development of drug resistance make it urgent to develop new drugs against methicillin-resistant Staphylococcus aureus (MRSA). The re-development of the antibacterial activity of drugs that have already been proven safe for human use is an effective way. In this study, we discovered that the Src homology region 2 domain-containing phosphatase-1 (SHP-1) agonist SC-43, exhibits potent activity against Gram-positive bacteria, including MRSA. The mode of action studies revealed that SC-43 inhibits the key enzyme coproporphyrin ferrochelatase (CpfC) of the coproporphyrin-dependent (CPD) heme synthesis pathway and interferes with the bacterial porphyrin metabolism. The determination of the structure of CpfC derived from S. aureus (SACpfC) in this study allowed us to reveal the inhibitory effect of SC-43 at the molecular level. Animal experiments showed that SC-43 has the potential to become a new anti-MRSA drug. In conclusion, this study discovered a new anti-MRSA activity of a drug currently undergoing clinical trials and simultaneously verified the feasibility of developing new anti-Gram-positive bacteria drugs by inhibiting the CPD pathway.