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SARIYAR AKBULUT, BERNA

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SARIYAR AKBULUT

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BERNA

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2016 - 20202
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Author: ALTINIŞIK KAYA, FATMA ECE × Has files: true ×

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    PublicationOpen Access
    Identification of novel inhibitors of the ABC transporter BmrA
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-12) SARIYAR AKBULUT, BERNA; 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
    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.
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    PublicationOpen Access
    An evolutionarily conserved allosteric site modulates beta-lactamase activity
    (TAYLOR & FRANCIS LTD, 2016-11-03) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Altinisik, Fatma Ece; Vardar Ulu, Didem; Ozkirimli Olmez, Elif; Akbulut, Berna Sariyar
    Declining efficiency of antibiotic-inhibitor combinatorial therapies in treating beta-lactamase mediated resistance necessitates novel inhibitor development. Allosteric inhibition offers an alternative to conventional drugs that target the conserved active site. Here, we show that the evolutionarily conserved PWP triad located at the N-terminus of the H10 helix directly interacts with the allosteric site in TEM-1 beta-lactamase and regulates its activity. While point mutations in the PWP triad preserve the overall secondary structures around the allosteric site, they result in a more open and dynamic global structure with decreased chemical stability and increased aggregation propensity. These mutant enzymes with a less compact hydrophobic core around the allosteric site displayed significant activity loss. Detailed sequence and structure conservation analyses revealed that the PWP triad is an evolutionarily conserved motif unique to class A beta-lactamases aligning its allosteric site and hence is an effective potential target for enzyme regulation and selective drug design.