Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii

doi:10.1038/s41589-023-01349-8

. 2023 Nov;19(11):1342-1350.

doi: 10.1038/s41589-023-01349-8. Epub 2023 May 25.

Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii

Gary Liu^#¹, Denise B Catacutan^#¹, Khushi Rathod^#¹, Kyle Swanson², Wengong Jin², Jody C Mohammed¹, Anush Chiappino-Pepe^{3

4}, Saad A Syed⁵, Meghan Fragis^{1

6}, Kenneth Rachwalski¹, Jakob Magolan^{1

6}, Michael G Surette⁵, Brian K Coombes¹, Tommi Jaakkola², Regina Barzilay^{2

7}, James J Collins^{8

9

10

11}, Jonathan M Stokes¹²

Affiliations

¹ 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.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁵ Department of Medicine, Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
⁶ Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
⁷ Abdul Latif Jameel Clinic for Machine Learning in Health, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. jimjc@mit.edu.
⁹ Abdul Latif Jameel Clinic for Machine Learning in Health, Massachusetts Institute of Technology, Cambridge, MA, USA. jimjc@mit.edu.
¹⁰ Department of Biological Engineering, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. jimjc@mit.edu.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. jimjc@mit.edu.
¹² 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. stokesjm@mcmaster.ca.

^# Contributed equally.

PMID: 37231267
DOI: 10.1038/s41589-023-01349-8

Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii

Gary Liu et al. Nat Chem Biol. 2023 Nov.

. 2023 Nov;19(11):1342-1350.

doi: 10.1038/s41589-023-01349-8. Epub 2023 May 25.

Authors

Affiliations

¹ 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.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁵ Department of Medicine, Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
⁶ Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
⁷ Abdul Latif Jameel Clinic for Machine Learning in Health, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. jimjc@mit.edu.
⁹ Abdul Latif Jameel Clinic for Machine Learning in Health, Massachusetts Institute of Technology, Cambridge, MA, USA. jimjc@mit.edu.
¹⁰ Department of Biological Engineering, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. jimjc@mit.edu.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. jimjc@mit.edu.
¹² 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. stokesjm@mcmaster.ca.

^# Contributed equally.

PMID: 37231267
DOI: 10.1038/s41589-023-01349-8

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.

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Comment in

A new antibiotic for A. baumannii.
Crunkhorn S. Crunkhorn S. Nat Rev Drug Discov. 2023 Jul;22(7):538. doi: 10.1038/d41573-023-00090-0. Nat Rev Drug Discov. 2023. PMID: 37286781 No abstract available.

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References

1. Antunes, L. C. S., Visca, P. & Towner, K. J. Acinetobacter baumannii: evolution of a global pathogen. Pathog. Dis. 71, 292–301 (2014). - PubMed
1. 2020 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis (World Health Organization, 2021); https://www.who.int/publications/i/item/9789240021303
1. Walsh, C. Where will new antibiotics come from? Nat. Rev. Microbiol. 1, 65–70 (2003). - PubMed
1. Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov. 14, 529–542 (2015). - PubMed
1. Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 180, 688–702 (2020). - PubMed - PMC

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[1] Antunes, L. C. S., Visca, P. & Towner, K. J. Acinetobacter baumannii: evolution of a global pathogen. Pathog. Dis. 71, 292–301 (2014). - PubMed

[2] Antunes, L. C. S., Visca, P. & Towner, K. J. Acinetobacter baumannii: evolution of a global pathogen. Pathog. Dis. 71, 292–301 (2014). - PubMed

[3] 2020 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis (World Health Organization, 2021); https://www.who.int/publications/i/item/9789240021303

[4] 2020 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis (World Health Organization, 2021); https://www.who.int/publications/i/item/9789240021303

[5] Walsh, C. Where will new antibiotics come from? Nat. Rev. Microbiol. 1, 65–70 (2003). - PubMed

[6] Walsh, C. Where will new antibiotics come from? Nat. Rev. Microbiol. 1, 65–70 (2003). - PubMed

[7] Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov. 14, 529–542 (2015). - PubMed

[8] Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov. 14, 529–542 (2015). - PubMed

[9] Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 180, 688–702 (2020). - PubMed - PMC

[10] Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 180, 688–702 (2020). - PubMed - PMC

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Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii

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