A Deep Learning Approach to Antibiotic Discovery
Author(s)Stokes, Jonathan; Yang, Kevin; Swanson, Kyle; Jin, Wengong; Cubillos, Andres Fernando; Donghia, Nina; MacNair, Craig R.; French, Shawn; Carfrae, Lindsey A.; Bloom-Ackermann, Zohar; Tran, Victoria M.; Chiappino-Pepe, Anush; Badran, Ahmed; Andrews, Ian W.; Chory, Emma J; Church, George M.; Brown, Eric D.; Jaakkola, Tommi S.; Barzilay, Regina; Collins, James J.; ... Show more Show less
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Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub—halicin—that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules. A trained deep neural network predicts antibiotic activity in molecules that are structurally different from known antibiotics, among which Halicin exhibits efficacy against broad-spectrum bacterial infections in mice.
DepartmentMassachusetts Institute of Technology. Institute for Medical Engineering and Science; Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Stokes, Jonathan M. et al. "A Deep Learning Approach to Antibiotic Discovery." 180, 4 (February 2020): 688-702 © 2020 Elsevier
Author's final manuscript