Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA

Zbigniew M. Darzynkiewicz, Adam T. Green, Narges Abdali, Anthony Hazel, Ronnie L. Fulton, Joseph Kimball, Zygmunt Gryczynski, James C. Gumbart, Jerry M. Parks, Jeremy C. Smith, Helen I. Zgurskaya

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Abstract

The overexpression of multidrug efflux pumps is an important mechanism of clinical resistance in Gram-negative bacteria. Recently, four small molecules were discovered that inhibit efflux in Escherichia coli and interact with the AcrAB-TolC efflux pump component AcrA. However, the binding site(s) for these molecules was not determined. Here, we combine ensemble docking and molecular dynamics simulations with tryptophan fluorescence spectroscopy, site-directed mutagenesis, and antibiotic susceptibility assays to probe binding sites and effects of binding of these molecules. We conclude that clorobiocin and SLU-258 likely bind at a site located between the lipoyl and β-barrel domains of AcrA.

Original languageEnglish
Pages (from-to)648-658
Number of pages11
JournalBiophysical Journal
Volume116
Issue number4
DOIs
StatePublished - 19 Feb 2019

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Darzynkiewicz, Z. M., Green, A. T., Abdali, N., Hazel, A., Fulton, R. L., Kimball, J., Gryczynski, Z., Gumbart, J. C., Parks, J. M., Smith, J. C., & Zgurskaya, H. I. (2019). Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA. Biophysical Journal, 116(4), 648-658. https://doi.org/10.1016/j.bpj.2019.01.010