Artificial intelligence using a latent diffusion model enables the generation of diverse and potent antimicrobial...

Artificial intelligence holds great promise for the design of antimicrobial peptides (AMPs); however, current models face limitations in generating AMPs with sufficient novelty and diversity, and they are rarely applied to the generation of antifungal peptides. Here, we develop an alternative pipeline grounded in a diffusion model and molecular dynamics for the de novo design of AMPs. The peptides generated by our pipeline have lower similarity and identity than those of other reported methodologies. Among the 40 peptides synthesized for an experimental validation, 25 exhibit either antibacterial or antifungal activity. AMP-29 shows selective antifungal activity against Candida glabrata and in vivo antifungal efficacy in a murine skin infection model. AMP-24 exhibits potent in vitro activity against Gram-negative bacteria and in vivo efficacy against both skin and lung Acinetobacter baumannii infection models. The proposed approach offers a pipeline for designing diverse AMPs to counteract the threat of antibiotic resistance.