Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii.

Journal: Nature chemical biology
Published Date: May 25, 2023

Abstract

Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new antibacterial molecules. Here we screened ~7,500 molecules for those that inhibited the growth of A. baumannii in vitro. We trained a neural network with this growth inhibition dataset and performed in silico predictions for structurally new molecules with activity against A. baumannii. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against A. baumannii. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE. Moreover, abaucin could control an A. baumannii infection in a mouse wound model. This work highlights the utility of machine learning in antibiotic discovery and describes a promising lead with targeted activity against a challenging Gram-negative pathogen.

Authors

  • Gary Liu
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Denise B Catacutan
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Khushi Rathod
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Kyle Swanson
  • Wengong Jin
    Computer Science and Artificial Intelligence Laboratory , Massachusetts Institute of Technology , 77 Massachusetts Avenue , Cambridge , MA 02139 , USA . Email: regina@csail.mit.edu.
  • Jody C Mohammed
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Anush Chiappino-Pepe
    Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Saad A Syed
    Department of Medicine, Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
  • Meghan Fragis
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Kenneth Rachwalski
    David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Jakob Magolan
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Michael G Surette
    Department of Medicine, Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
  • Brian K Coombes
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Tommi Jaakkola
    Computer Science and Artificial Intelligence Laboratory , MIT , Cambridge , Massachusetts 02139 , United States.
  • Regina Barzilay
    Computer Science and Artificial Intelligence Laboratory , Massachusetts Institute of Technology , 77 Massachusetts Avenue , Cambridge , MA 02139 , USA . Email: regina@csail.mit.edu.
  • James J Collins
    Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Jonathan M Stokes
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Machine Learning for Pharmaceutical Discovery and Synthesis Consortium, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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