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 (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.
Authors
- Hongxia Ma (ORCID: https://orcid.org/0000-0003-0165-4412)
- Heng Wang (ORCID: https://orcid.org/0000-0002-6543-2723)
- Xiaodi Niu (ORCID: https://orcid.org/0000-0001-6640-0427)
- Xuming Deng (ORCID: https://orcid.org/0000-0001-6411-1074)
- Xinyue He (ORCID: https://orcid.org/0000-0002-2214-9338)
- Lei Xu (ORCID: https://orcid.org/0009-0000-2316-2350)
- Yang Wang (ORCID: https://orcid.org/0000-0002-5928-9377)
- Nan Wang (ORCID: https://orcid.org/0000-0002-9936-9179)
- Jianfeng Wang (ORCID: https://orcid.org/0000-0001-8311-0894)
- Lanqiao Wang
- Lingcong Kong (ORCID: https://orcid.org/0000-0001-6884-4005)
Institutions
- Jilin University (CN)
- Jilin Agricultural University (CN)
- China Agricultural University (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1038/s42003-025-09251-w
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Fundamental Research Funds for the Central Universities