Uncovering evolutionarily remote and highly potent antimicrobial peptides with protein language models

Identifying evolutionarily remote antimicrobial peptides (AMPs) is crucial for discovering underexplored clinical candidates to combat antibiotic resistance. Existing experimental and computational methods are limited by their reliance on sequence identity to known AMPs, missing distant homologues. Here we introduce HMD-AMP, a protein language model-based approach for AMP discovery. HMD-AMP outperforms previous methods in identifying evolutionarily distant AMPs and enables the discovery of unknown and highly potent AMPs from metagenomic data. Applied to host and gut microorganism genomes of nine mammals, HMD-AMP revealed over 37 million predicted AMPs. Of 91 high-confidence sequences experimentally validated, 74 showed strong antibacterial activity and 48 were evolutionarily remote from known AMPs. Four of these AMPs exhibited broad-spectrum antibacterial activity at low effective concentrations and showed low toxicity, with the most potent peptide demonstrating therapeutic efficacy in a mouse model of peritoneal Escherichia coli infection. This study introduces an effective strategy to uncover AMPs.