Identification of novel inhibitors of the ABC transporter BmrA
| Autor: | Duygu Senturk, Berna Sariyar Akbulut, Jean-Michel Jault, Fatma Ece Altinisik Kaya, Pemra Ozbek, Tihomir Tomašič, Rok Frlan, Onur Serçinoğlu, Fatma Gizem Avci, Cédric Orelle |
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| Přispěvatelé: | Recep Tayyip Erdogan University, Marmara University [Kadıköy - İstanbul], Üsküdar university, University of Ljubljana, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Sercinoglu, Onur, Senturk, Duygu, Kaya, Fatma Ece Altinisik, Avci, Fatma Gizem, Frlan, Rok, Tomasic, Tihomir, Ozbek, Pemra, Orelle, Cedric, Jault, Jean-Michel, Akbulut, Berna Sariyar |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Protein Conformation
Antibiotic resistance Drug Evaluation Preclinical ATP-binding cassette transporter [CHIM.THER]Chemical Sciences/Medicinal Chemistry Ligands NUCLEOTIDE-BINDING 01 natural sciences Biochemistry Ethidium Drug Discovery Efflux pump inhibitors Chemistry MULTIDRUG EFFLUX PUMP P-GLYCOPROTEIN Chemotheca ACRB Small molecule 3. Good health Molecular Docking Simulation BmrA Cyclic nucleotide-binding domain Molecular docking Lipinski's rule of five Efflux Bacillus subtilis Virtual screening BACILLUS-SUBTILIS Small Molecule Libraries Bacterial Proteins Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Amino Acid Sequence ATP-BINDING REVERSAL AGENTS Molecular Biology STAPHYLOCOCCUS-AUREUS DRUG-RESISTANCE 010405 organic chemistry Organic Chemistry Membrane Transport Proteins Nucleotide-binding domain IN-SILICO [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology 0104 chemical sciences Multiple drug resistance 010404 medicinal & biomolecular chemistry ATP-Binding Cassette Transporters Protein Multimerization |
| Zdroj: | Bioorganic Chemistry Bioorganic Chemistry, Elsevier, 2020, 105, pp.104452. ⟨10.1016/j.bioorg.2020.104452⟩ |
| ISSN: | 0045-2068 1090-2120 |
| DOI: | 10.1016/j.bioorg.2020.104452⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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