De Novo Multi‐Mechanism Antimicrobial Peptide Design via Multimodal Deep Learning

ABSTRACT Artificial intelligence (AI)‐driven discovery of antimicrobial peptides (AMPs) is yet to fully utilize their three‐dimensional (3D) structural characteristics, microbial species‐specific antimicrobial activities, and mechanisms. Here, we constructed a QLAPD database comprising the sequence, structures, and antimicrobial properties of 12 914 AMPs. QLAPD underlies a multimodal, multitask, multilabel, and conditionally controlled AMP discovery (M3‐CAD) pipeline, proposed for the de novo design of multi‐mechanism AMPs to combat multidrug‐resistant organisms (MDROs). This pipeline integrates generation, regression, and classification modules, using an innovative 3D voxel coloring method to capture the nuanced physicochemical context of amino acids, thus enhancing structural characterizations. QLX‐3DV‐1 and QLX‐3DV‐2, identified through M3‐CAD, were found to demonstrate multiple antimicrobial mechanisms, notable activity against MDROs, and low toxicity. In vivo experiments were used to validate their antimicrobial effects with limited local and systemic toxicity. Overall, integrating 3D features, species‐specific antimicrobial activities, and mechanisms enhanced AI‐driven AMP discovery, making the M3‐CAD pipeline a viable tool for de novo AMP design.