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

Journal Article · Fri Feb 01 00:00:00 EST 2019 · Biophysical Journal

DOI:https://doi.org/10.1016/j.bpj.2019.01.010· OSTI ID:1600560

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

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. Nonetheless, the binding site(s) for these molecules was not determined. With this research, 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.

• Research Organization: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC05-00OR22725; MCB-1452464; OCI-1053575
• OSTI ID: 1600560
• Alternate ID(s): OSTI ID: 1503982
• Journal Information: Biophysical Journal, Journal Name: Biophysical Journal Vol. 116 Journal Issue: 4; ISSN 0006-3495
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES