AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria.

Abstract

Host defense peptide (HDP)-mimicking polymers are promising therapeutic alternatives to antibiotics and have large-scale untapped potential. Artificial intelligence (AI) exhibits promising performance on large-scale chemical-content design, however, existing AI methods face difficulties on scarcity data in each family of HDP-mimicking polymers (<10²), much smaller than public polymer datasets (>10⁵), and multi-constraints on properties and structures when exploring high-dimensional polymer space. Herein, we develop a universal AI-guided few-shot inverse design framework by designing multi-modal representations to enrich polymer information for predictions and creating a graph grammar distillation for chemical space restriction to improve the efficiency of multi-constrained polymer generation with reinforcement learning. Exampled with HDP-mimicking β-amino acid polymers, we successfully simulate predictions of over 10⁵ polymers and identify 83 optimal polymers. Furthermore, we synthesize an optimal polymer DM_0.8iPen_0.2 and find that this polymer exhibits broad-spectrum and potent antibacterial activity against multiple clinically isolated antibiotic-resistant pathogens, validating the effectiveness of AI-guided design strategy.