The rise of antibiotic resistance has turned up the pressure for the discovery of novel therapies against Gram-negative pathogens. Unfortunately, a lack of understanding how and why only certain molecules can penetrate bacteria has greatly hindered the development of new drugs. The first large-scale prospective study of small-molecule accumulation in <i>Escherichia coli</i> was conducted using a highly diverse compound library. Results from this study were used to train a predicting model of accumulation. By measuring variable importance in this model, we identified four factors as significantly contributing to small-molecule accumulation: presence of a primary amine, amphiphilicity, flexibility, and three-dimensionality. The molecular mechanism by which these factors contribute to accumulation was evaluated via a series of molecular dynamics simulations of OmpF, the principle mode of entry for small-molecules into <i>E. coli</i>. Further, a web application was developed to facilitate predict high value candidates for conversion into broad spectrum agents (entry-way.org). Using this tool, several antibiotics with activity against only Gram-positive bacteria were modified in accord with the newly learned design principles. The bioactivity and mechanism of action of active compounds were evaluated so as to assess translation potential.

Predicting accumulation in Gram-negative bacteria to design better antibiotics

256th National Meeting (2018)

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