Identification of novel inhibitors of the ABC transporter BmrA.

Autor: Serçinoğlu O; Department of Bioengineering, Recep Tayyip Erdogan University, Fener 53100, Rize, Turkey., Senturk D; Department of Bioengineering, Marmara University, Kadikoy 34722, Istanbul, Turkey., Altinisik Kaya FE; Department of Bioengineering, Marmara University, Kadikoy 34722, Istanbul, Turkey., Avci FG; Department of Bioengineering, Uskudar University, Uskudar 34662, Istanbul, Turkey., Frlan R; University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia., Tomašič T; University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia., Ozbek P; Department of Bioengineering, Marmara University, Kadikoy 34722, Istanbul, Turkey., Orelle C; University of Lyon, CNRS, UMR5086 'Molecular Microbiology and Structural Biochemistry', 7 passage du Vercors, 69367 Lyon Cedex 7, France., Jault JM; University of Lyon, CNRS, UMR5086 'Molecular Microbiology and Structural Biochemistry', 7 passage du Vercors, 69367 Lyon Cedex 7, France., Sariyar Akbulut B; Department of Bioengineering, Marmara University, Kadikoy 34722, Istanbul, Turkey. Electronic address: berna.akbulut@marmara.edu.tr.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Dec; Vol. 105, pp. 104452. Date of Electronic Publication: 2020 Nov 04.
DOI: 10.1016/j.bioorg.2020.104452
Abstrakt: The resistance of microbes to commonly used antibiotics has become a worldwide health problem. A major underlying mechanism of microbial antibiotic resistance is the export of drugs from bacterial cells. Drug efflux is mediated through the action of multidrug resistance efflux pumps located in the bacterial cell membranes. The critical role of bacterial efflux pumps in antibiotic resistance has directed research efforts to the identification of novel efflux pump inhibitors that can be used alongside antibiotics in clinical settings. Here, we aimed to find potential inhibitors of the archetypical ATP-binding cassette (ABC) efflux pump BmrA of Bacillus subtilis via virtual screening of the Mu.Ta.Lig. Chemotheca small molecule library. Molecular docking calculations targeting the nucleotide-binding domain of BmrA were performed using AutoDock Vina. Following a further drug-likeness filtering step based on Lipinski's Rule of Five, top 25 scorers were identified. These ligands were then clustered into separate groups based on their contact patterns with the BmrA nucleotide-binding domain. Six ligands with distinct contact patterns were used for further in vitro inhibition assays based on intracellular ethidium bromide accumulation. Using this methodology, we identified two novel inhibitors of BmrA from the Chemotheca small molecule library.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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