Work

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

Year: 2025

Type: article

Abstract: 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. Lysosomal activation via the MDM2-P53-V-ATPase axis unveils a potent host-directed strategy for eradicating intracellular pathogens and potentiating conventional antimicrobial therapy.

Source: Communications Biology

DOI: 10.1038/s42003-025-09251-w