biostudies-literatureWang HNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)16https://www.ebi.ac.uk/biostudies/studies/S-EPMC12769697biostudies-literatureUnknown9(1)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 lCommunications biologyMDM2-P53-V-ATPases axis driven by dehydroevodiamine to fight intracellular bacterial infection.PMC12769697U22A20523Xu LWang NKong LHe XMa HWang HWang YWang JNiu XDeng XWang LfalseMDM2-P53-V-ATPases axis driven by dehydroevodiamine to fight intracellular bacterial infection.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 l2025-01-01T00:00:00Z2025 Dec2026-06-06T11:08:01.434Z2026-05-29T03:12:39.434ZS-EPMC127696974139071110.1038/s42003-025-09251-w