MDM2 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 as a broad-spectrum host-directed antibiotic that inhibits intracellular bacterial replication and acts synergistically with antibiotics both in vitro and in vivo. Structural analyses reveal that DEHD directly binds to MDM2, activating the MDM2-p53-V-ATPase axis to maintain lysosomal acidity via 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 infection models. Our work establishes lysosomal activation via the MDM2-p53-V-ATPase axis as a potent host-directed strategy, with DEHD representing a promising lead compound against intracellular infections.