General platform for systematic quantitative evaluation of small-molecule permeability in bacteria Journal Article
| Authors: | Davis, T. D.; Gerry, C. J.; Tan, D. S. |
| Article Title: | General platform for systematic quantitative evaluation of small-molecule permeability in bacteria |
| Abstract: | The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibiotics. Antibacterials are known to have vastly different structural and physicochemical properties compared to nonantiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate the penetration of diverse compounds into bacteria with distinct cellular envelopes. Intracellular compound accumulation is quantitated using LC-MS/MS, then PCA and Pearson pairwise correlations are used to identify structural and physicochemical parameters that correlate with accumulation. An initial study using 10 sulfonyladenosines in Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis has identified nonobvious correlations between chemical structure and permeability that differ among the various bacteria. Effects of cotreatment with efflux pump inhibitors were also investigated. This sets the stage for use of this platform in larger prospective analyses of diverse chemotypes to identify global relationships between chemical structure and bacterial permeability that would enable the development of predictive tools to accelerate antibiotic drug discovery. |
| Keywords: | controlled study; antibiotic agent; nonhuman; quantitative analysis; escherichia coli; tandem mass spectrometry; hydrogen bond; liquid chromatography; physical chemistry; cell membrane permeability; bacillus subtilis; mycobacterium smegmatis; hydrogen; membrane structure; hydrophobicity; bacterial membrane; article |
| Journal Title: | ACS Chemical Biology |
| Volume: | 9 |
| Issue: | 11 |
| ISSN: | 1554-8929 |
| Publisher: | American Chemical Society |
| Date Published: | 2014-11-21 |
| Start Page: | 2535 |
| End Page: | 2544 |
| Language: | English |
| DOI: | 10.1021/cb5003015 |
| PROVIDER: | scopus |
| PMCID: | PMC4245172 |
| PUBMED: | 25198656 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
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