Discovery of AMPs from random peptides via deep learning-based model and biological activity validation

• Published in: European journal of medicinal chemistry 2024-11, Vol.277, p.116797, Article 116797
• Main Authors: Du, Jun, Yang, Changyan, Deng, Yabo, Guo, Hai, Gu, Mengyun, Chen, Danna, Liu, Xia, Huang, Jinqi, Yan, Wenjin, Liu, Jian
• Format: Article
• Language: English
• Subjects: Antimicrobial peptides; Artificial intelligence (AI); Deep learning; Drug-resistant bacteria; Wound infection modeling
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116797

The ample peptide field is the best source for discovering clinically available novel antimicrobial peptides (AMPs) to address emerging drug resistance. However, discovering novel AMPs is complex and expensive, representing a major challenge. Recent advances in artificial intelligence (AI) have significantly improved the efficiency of identifying antimicrobial peptides from large libraries, whereas using random peptides as negative data increases the difficulty of discovering antimicrobial peptides from random peptides using discriminative models. In this study, we constructed three multi-discriminator models using deep learning and successfully screened twelve AMPs from a library of 30,000 random peptides. three candidate peptides (P2, P11, and P12) were screened by antimicrobial experiments, and further experiments showed that they not only possessed excellent antimicrobial activity but also had extremely low hemolytic activity. Mechanistic studies showed that these peptides exerted their bactericidal effects through membrane disruption, thus reducing the possibility of bacterial resistance. Notably, peptide 12 (P12) showed significant efficacy in a mouse model of Staphylococcus aureus wound infection with low toxicity to major organs at the highest tested dose (400 mg/kg). These results suggest deep learning-based multi-discriminator models can identify AMPs from random peptides with potential clinical applications. [Display omitted] •Multi-discriminated models were constructed and used to screen 12 candidate peptides from random peptides.•Most candidate peptides exhibited higher β-strain content compared to α-helix.•Peptides 2, 11, and 12 exhibited broad-spectrum antibacterial activity and low hemolytic toxicity.•Peptide 12 exhibited excellent in vivo antibacterial activity and less damage to the major organs of mice.