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In silico screening for antibiotic escort molecules to overcome efflux

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Abstract

Resistance to antibiotics is a growing problem worldwide and occurs in part due to the overexpression of efflux pumps responsible for the removal of antibiotics from bacterial cells. The current study examines complex formation between efflux pump substrates and escort molecules as a criterion for an in silico screening method for molecules that are able to potentiate antibiotic activities. Initially, the SUPERDRUG database was queried to select molecules that were similar to known multidrug resistance (MDR) modulators. Molecular interaction fields generated by GRID and the docking module GLUE were used to calculate the interaction energies between the selected molecules and the antibiotic norfloxacin. Ten compounds forming the most stable complexes with favourable changes to the norfloxacin molecular properties were tested for their potentiation ability by efflux pump modulation assays. Encouragingly, two molecules were proven to act as efflux pump modulators, and hence provide evidence that complex formation between a substrate and a drug can be used for in silico screening for novel escort molecules.

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Acknowledgments

The authors would like to thank the Engineering and Physical Sciences Research Council (EPSRC) and the School of Pharmacy for providing financial support and studentship funding.

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Authors and Affiliations

  1. The School of Pharmacy, University of London, 29–39 Brunswick Square, London, WC1N 1AX, UK

    Sheikh S. Rahman, Ivana Simovic, Simon Gibbons & Mire Zloh

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  1. Sheikh S. Rahman
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  2. Ivana Simovic
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  3. Simon Gibbons
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  4. Mire Zloh
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Correspondence to Mire Zloh.

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Rahman, S.S., Simovic, I., Gibbons, S. et al. In silico screening for antibiotic escort molecules to overcome efflux. J Mol Model 17, 2863–2872 (2011). https://doi.org/10.1007/s00894-011-0978-7

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