A Deep Learning Approach to Antibiotic Discovery

Cell. 2020 Feb 20;180(4):688-702.e13. doi: 10.1016/j.cell.2020.01.021.

Abstract

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.

Keywords: antibiotic resistance; antibiotic tolerance; antibiotics; drug discovery; machine learning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cheminformatics / methods
  • Clostridioides difficile / drug effects
  • Databases, Chemical
  • Drug Discovery / methods*
  • Machine Learning*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*

Substances

  • Anti-Bacterial Agents
  • SU 3327
  • Small Molecule Libraries
  • Thiadiazoles