Discovery and artificial intelligence-guided mechanistic elucidation of a narrow-spectrum antibiotic

A large-scale screening of 10,747 bioactive molecules led to the discovery of enterololin, a novel antibacterial compound with narrow-spectrum activity specifically targeting Enterobacteriaceae such as E. coli, including adherent-invasive E. coli (AIEC) linked to inflammatory bowel disease. When combined with the polymyxin analogue SPR741, enterololin overcomes bacterial resistance by disrupting lipoprotein trafficking via the LolCDE complex, with mutations in lolC and lolE conferring resistance. The compound demonstrated low toxicity, effectively reduced AIEC infection in mice, and preserved gut microbiome diversity, offering a promising microbiome-sparing therapeutic candidate. The study also underscores the value of deep learning in elucidating mechanisms of action and accelerating targeted antibiotic discovery.