Property space mapping of Pseudomonas aeruginosa permeability to small molecules

Leus, Inga V.; Weeks, Jon W.; Bonifay, Vincent; Shen, Yue; Yang, Liang; Cooper, Connor J.; Nash, Dinesh; Duerfeldt, Adam S.; Smith, Jeremy C.; Parks, Jerry M.; Rybenkov, Valentin V.; Zgurskaya, Helen I.

doi:10.1038/s41598-022-12376-1

Title: Property space mapping of Pseudomonas aeruginosa permeability to small molecules

Journal Article · Tue May 17 00:00:00 EDT 2022 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-022-12376-1· OSTI ID:1869114

Leus, Inga V. ^[1]; Weeks, Jon W. ^[1]; Bonifay, Vincent ^[1]; Shen, Yue ^[2]; Yang, Liang ^[1]; Cooper, Connor J. ^[3]; Nash, Dinesh ^[1]; Duerfeldt, Adam S. ^[4]; Smith, Jeremy C. ^[2];

^[3]; Rybenkov, Valentin V. ^[1]; Zgurskaya, Helen I. ^[1]

Univ. of Oklahoma, Norman, OK (United States)
Univ. of Tennessee, Knoxville, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Minnesota, Minneapolis, MN (United States)

Two membrane cell envelopes act as selective permeability barriers in Gram-negative bacteria, protecting cells against antibiotics and other small molecules. Significant efforts are being directed toward understanding how small molecules permeate these barriers. In this study, we developed an approach to analyze the permeation of compounds into Gram-negative bacteria and applied it to Pseudomonas aeruginosa, an important human pathogen notorious for resistance to multiple antibiotics. The approach uses mass spectrometric measurements of accumulation of a library of structurally diverse compounds in four isogenic strains of P. aeruginosa with varied permeability barriers. We further developed a machine learning algorithm that generates a deterministic classification model with minimal synonymity between the descriptors. This model predicted good permeators into P. aeruginosa with an accuracy of 89% and precision above 58%. The good permeators are broadly distributed in the property space and can be mapped to six distinct regions representing diverse chemical scaffolds. We posit that this approach can be used for more detailed mapping of the property space and for rational design of compounds with high Gram-negative permeability.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC); Defense Threat Reduction Agency (DTRA); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-00OR22725; HDTRA1-14-1-0019; RO1-AI052293; RO1-AI132836

OSTI ID:: 1869114

Journal Information:: Scientific Reports, Vol. 12, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Property space mapping of Pseudomonas aeruginosa permeability to small molecules

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