当前位置: X-MOL 学术Bioorgan. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Identification of novel inhibitors of the ABC transporter BmrA
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-11-04 , DOI: 10.1016/j.bioorg.2020.104452
Onur Serçinoğlu , Duygu Senturk , Fatma Ece Altinisik Kaya , Fatma Gizem Avci , Rok Frlan , Tihomir Tomašič , Pemra Ozbek , Cédric Orelle , Jean-Michel Jault , Berna Sariyar Akbulut

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.



中文翻译:

鉴定ABC转运蛋白BmrA的新型抑制剂

微生物对常用抗生素的耐药性已成为全球性的健康问题。微生物抗生素抗性的主要潜在机制是细菌细胞中药物的输出。药物外排是通过位于细菌细胞膜上的多药耐药外排泵的作用介导的。细菌外排泵在抗生素耐药性中的关键作用已将研究工作定向到鉴定可与抗生素一起在临床环境中使用的新型外排泵抑制剂。在这里,我们旨在寻找枯草芽孢杆菌原型ATP结合盒(ABC)外排泵BmrA的潜在抑制剂。通过对Mu.Ta.Lig的虚拟筛选 Chemotheca小分子文库。使用AutoDock Vina进行了针对BmrA核苷酸结合域的分子对接计算。在根据Lipinski的“五则规则”进行进一步的类药物过滤步骤之后,确定了排名前25位的得分手。然后,根据这些配体与BmrA核苷酸结合结构域的接触方式,将它们配成单独的组。基于细胞内溴化乙锭积累,将六个具有不同接触模式的配体用于进一步的体外抑制试验。使用这种方法,我们从Chemotheca小分子文库中鉴定了两种新型的BmrA抑制剂。

更新日期:2020-11-16
down
wechat
bug