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<p>Host-directed antibacterial compounds remain underdeveloped for intracellular pathogens. Here, we identify Dehydroevodiamine (DEHD) as a broad-spectrum host-directed antibiotics that inhibits intracellular bacterial replication (<i>Salmonella</i>, <i>E. coli</i>, <i>S. aureus</i>, etc.) and synergizes with antibiotics in vitro and in vivo. Structural analyses reveal DEHD directly binds MDM2 (KD=68.34 μM), activating the MDM2-P53-V-ATPases axis to maintain lysosomal acidity through V-ATPase activity and induce mTOR-dependent autophagy. This mechanism enhances antibiotic efficacy against resistant pathogens, reducing mortality from 90% to 10% in lethal murine infections. Our work establishes lysosomal activation via the MDM2-P53-V-ATPases axis as a potent host-directed strategy, with DEHD providing a promising lead compound against intracellular infections.</p><p></p>

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MDM2-P53-V-ATPases axis driven by dehydroevodiamine to fight intracellular bacterial infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • Heng Wang,
  • Xinyue He,
  • Lanqiao Wang,
  • Nan Wang,
  • Xiaodi Niu,
  • Lei Xu,
  • Lingcong Kong,
  • Hongxia Ma,
  • Yang Wang,
  • Xuming Deng,
  • Jianfeng Wang

摘要

Host-directed antibacterial compounds remain underdeveloped for intracellular pathogens. Here, we identify Dehydroevodiamine (DEHD) as a broad-spectrum host-directed antibiotics that inhibits intracellular bacterial replication (Salmonella, E. coli, S. aureus, etc.) and synergizes with antibiotics in vitro and in vivo. Structural analyses reveal DEHD directly binds MDM2 (KD=68.34 μM), activating the MDM2-P53-V-ATPases axis to maintain lysosomal acidity through V-ATPase activity and induce mTOR-dependent autophagy. This mechanism enhances antibiotic efficacy against resistant pathogens, reducing mortality from 90% to 10% in lethal murine infections. Our work establishes lysosomal activation via the MDM2-P53-V-ATPases axis as a potent host-directed strategy, with DEHD providing a promising lead compound against intracellular infections.