A Foundation Model Identifies Broad-Spectrum Antimicrobial Peptides against Drug-Resistant Bacterial Infection
Development of potent and broad-spectrum antimicrobial peptides (AMPs) could help overcome the antimicrobial resistance crisis. We develop a peptide language-based deep generative framework (deepAMP) for identifying potent, broad-spectrum AMPs. Using deepAMP to reduce antimicrobial resistance and enhance the membrane-disrupting abilities of AMPs, we identify, synthesize, and experimentally test 18 T1-AMP (Tier 1) and 11 T2-AMP (Tier 2) candidates in a two-round design and by employing cross-optimization-validation. More than 90% of the designed AMPs show a better inhibition than penetratin in both Gram-positive (i.e., S. aureus) and Gram-negative bacteria (i.e., K. pneumoniae and P. aeruginosa). T2-9 shows the strongest antibacterial activity, comparable to FDA-approved antibiotics. We show that three AMPs (T1-2, T1-5 and T2-10) significantly reduce resistance to S. aureus compared to ciprofloxacin and are effective against skin wound infection in a female wound mouse model infected with P. aeruginosa. In summary, deepAMP expedites discovery of effective, broad-spectrum AMPs against drug-resistant bacteria.
Authors
- Feixiong Cheng (ORCID: https://orcid.org/0000-0002-1736-2847)
- Junfeng Shi (ORCID: https://orcid.org/0000-0001-7705-8866)
- Ruth Nussinov (ORCID: https://orcid.org/0000-0002-8115-6415)
- Xiangxiang Zeng (ORCID: https://orcid.org/0000-0001-6201-0114)
- Zhenlu Li (ORCID: https://orcid.org/0000-0003-2101-8237)
- Jun Shen (ORCID: https://orcid.org/0000-0002-9403-7140)
- Zhuole Wang
- Yun Li (ORCID: https://orcid.org/0000-0003-4489-1143)
- Tingting Li (ORCID: https://orcid.org/0000-0002-2303-6394)
- Xiaoyan Luo (ORCID: https://orcid.org/0009-0006-3859-9081)
- Xiaoli Luo
- Xuanbai Ren
- Dan Yuan (ORCID: https://orcid.org/0000-0003-2831-0388)
Institutions
- Cleveland Clinic (US)
- Central South University (CN)
- Tianjin University (CN)
- Tel Aviv University (IL)
- Hunan University (CN)
- Hunan Normal University (CN)
- Cleveland Clinic Lerner College of Medicine (US)
- Key Laboratory of Guangdong Province (CN)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Xiangya Hospital Central South University (CN)
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1038/s41467-024-51933-2
- Citations
- 83
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 28.61
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Cancer Institute