A Foundation Model Identifies Broad-Spectrum Antimicrobial Peptides against Drug-Resistant Bacterial Infection

Tingting Li, Xuanbai Ren, Xiaoli Luo, Zhuole Wang, Zhenlu Li, Xiaoyan Luo, Jun Shen, Yun Li, Dan Yuan, Ruth Nussinov, Xiangxiang Zeng (), Junfeng Shi () and Feixiong Cheng ()
Additional contact information
Tingting Li: Hunan University
Xuanbai Ren: Hunan University
Xiaoli Luo: Hunan University
Zhuole Wang: Hunan University
Zhenlu Li: Tianjin University
Xiaoyan Luo: Hunan University
Jun Shen: Hunan University
Yun Li: The 2nd Xiangya Hospital of Central South University
Dan Yuan: Hunan University
Ruth Nussinov: Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute
Xiangxiang Zeng: Hunan University
Junfeng Shi: Hunan University
Feixiong Cheng: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51933-2

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