期刊
BIOPHYSICAL JOURNAL
卷 116, 期 4, 页码 648-658出版社
CELL PRESS
DOI: 10.1016/j.bpj.2019.01.010
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资金
- National Institutes of Health, United States [AI052293]
- Department of Energy, United States [DE-AC05-00OR22725]
- National Science Foundation, United States [MCB-1452464]
- National Science Foundation [OCI-1053575]
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 beta-barrel domains of AcrA.
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