Deep learning–enabled discovery of antibiotics effective against Neisseria gonorrhoeae

作者：Melis N. Anahtar, Jacqueline A. Valeri, Seyed Majed Modaresi, Aarti Krishnan, Nina M. Donghia, Samantha G. Palace, Erica J. Zheng, Aakanksha Gulati, Alicia Jorgenson, Abidemi Junaid, Parijat Bandyopadhyay, Andreas Luttens, Krishna Suresh, Paige Edwards, Felix Wong, Yu Zhang, Danilo Ritz, Marion Gaborieau, Edmund Loh, Massimiliano Gaetani, Marie‐Stéphanie Aschtgen, Amir Ata Saei, Yonatan H. Grad, Donald E. Ingber, James J. Collins · 发表于：Science Translational Medicine · 年份：2026 · DOI：10.1126/scitranslmed.ads4699 · 被引用次数：2 · 研究领域：Reproductive tract infections research、vaccines and immunoinformatics approaches、Bacterial Infections and Vaccines

Neisseria gonorrhoeae is a common Gram-negative pathogen with increasing resistance to all recommended antibiotics. There is a critical need to improve the efficiency of the antibiotic hit discovery process to replenish the drug development pipeline. Here, we show that deep learning models can augment high-throughput screens to identify readily available molecules with narrow-spectrum activity against difficult-to-treat strains of N. gonorrhoeae . We phenotypically tested 38,650 small molecules for N. gonorrhoeae growth inhibition to train a predictive graph neural network (GNN) model. We benchmarked the model’s performance against other architectures, including a large language model, and found that GNNs more accurately identify active, drug-like molecules that are structurally distinct from the training set and known antibiotics. Using the model to virtually screen ~6 million compounds, we identified 213 compounds for experimental validation and found that 83 (39%) inhibited N. gonorrhoeae growth. Two of these compounds were structurally dissimilar to existing antibiotics, maintained potency against multidrug-resistant N. gonorrhoeae strains in vitro, exhibited promising selectivity indices, and were rapidly bactericidal with low frequencies of resistance. Proteomic studies revealed their distinct mechanisms of action, with one compound targeting alanine racemase, an enzyme involved in the essential process of peptidoglycan synthesis. Furthermore, the compounds showed early...