EBAMP: An efficient de novo broad-spectrum antimicrobial peptide discovery framework

  • Cell Rep. 2025 Sep 23;44(9):116215. doi: 10.1016/j.celrep.2025.116215.
Yunxiang Zhao  1 ,  Qian Li  2 ,  Mingyue Sun  3 ,  Yixin Su  4 ,  Xinxin Su  5 ,  Ling Jiang  6 ,  Xinran Zhang  2 ,  Yangyi Hu  7 ,  Boqian Wang  1 ,  Haoran Yu  6 ,  Qiang Zhang  8 ,  Zili Chai  1 ,  Ding Yao  3 ,  Yuhao Ren  2 ,  Wenhua Huang  2 ,  Yuan Jin  1 ,  Yutao Dou  9 ,  Dongsheng Li  5 ,  Zhen Huang  10 ,  Peng Liu  11 ,  Hongguang Ren  12 ,  Yongqiang Jiang  13
Affiliations
  • 1. Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China.
  • 2. State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
  • 3. School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
  • 4. School of Computer Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
  • 5. College of Computer, National University of Defence Technology, Changsha 410073, China.
  • 6. College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Centre, Hangzhou 311200, China; Zhejiang Key Laboratory of Intelligent Manufacturing for Functional Chemicals, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China.
  • 7. Department of Pharmaceutical Science, Beijing Institute of Radiation Medicine, Beijing 100850, China.
  • 8. ZJU-UIUC Institute, Zhejiang University, Haining 314400, China.
  • 9. College of Computer Science and Electronic Engineering, Hunan University, Changsha 410082, China.
  • 10. College of Computer, National University of Defence Technology, Changsha 410073, China. Electronic address: [email protected].
  • 11. State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: [email protected].
  • 12. Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China. Electronic address: [email protected].
  • 13. State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: [email protected].
PMID: 40906555 DOI: 10.1016/j.celrep.2025.116215
Abstract

De novo design of antimicrobial peptides (AMPs) is challenging due to the vast combinatorial space and unknown mechanisms. We propose EBAMP, a generative-discriminative framework for de novo broad-spectrum AMP design targeting bacteria and fungi. EBAMP combines a Transformer-based generative model with advanced feature-based screening to explore peptide space and select multiobjective candidates. Experimental testing of 256 designed sequences shows that 96 (37.5%) display bactericidal ability. The top 10 sequences exhibit low cytotoxicity, low hemolysis, and strong Antibacterial effect (2 μg/mL) against multidrug-resistant bacteria and fungi. In vivo mouse full-thickness wound Infection model demonstrates inhibitory effects against Acinetobacter baumannii (bacterium) and Candida auris (fungus), with therapeutic efficiency comparable to Antibiotics but lower resistance propensity. Alanine substitution analysis and molecular dynamics reveal functionally critical positions. EBAMP showcases large generative models for broad-spectrum AMP discovery and addresses Antibiotic resistance.

Keywords
CP: Microbiology; antimicrobial peptide; bacteria; broad spectrum; de novo design; drug resistance; fungi; generative-discriminative pipeline; large generative model.
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