Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of respectively. DZ-3 also potentiated tetracycline by 64-fold in AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in XU212 and RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

中文翻译：

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发现新型二氢萘-咪唑配体作为金黄色葡萄球菌多重耐药性 NorA 外排泵的潜在抑制剂：实验和计算机分子对接研究的结合

外排泵的过度表达是细菌表现出抗菌素耐药性（AMR）并导致全球出现多药耐药性（MDR）的主要机制。在这项工作中，设计、合成了与一些已知的外排泵抑制剂（EPI）结构相似的基于二氢萘基支架的咪唑衍生物库的抑制潜力，并针对外排泵抑制剂对过度表达的菌株进行了评估，以研究化合物和药物的协同作用。抗生素。在 15 种化合物中，有 4 种化合物（Dz-1、Dz-3、Dz-7 和 Dz-8）被发现具有高活性。 DZ-3 将环丙沙星、红霉素和四环素分别针对 1199B、XU212 和 RN4220 菌株的 MIC 调节了 128 倍。 DZ-3 还在 AG100 菌株中将四环素增强了 64 倍。 DZ-7 在 XU212 和 RN4220 菌株中将四环素和红霉素的 MIC 分别调节 128 倍。 DZ-1 和 DZ-8 显示 AG100 中四环素的 MIC 分别仅适度降低 16 倍和 8 倍。通过使用 NorA 过表达菌株 SA-1199B 进行的溴化乙锭外流抑制和积累研究，发现 DZ-3 是 NorA 的潜在抑制剂。 DZ-3 在对人体细胞无细胞毒性的浓度下显示出 EPI 活性，并且不具有任何抗菌活性。此外，还进行了DZ-3的分子对接研究，以了解DZ-3与蛋白质活性位点可能的结合位点。这些研究表明二氢萘支架可以作为开发有前景的 EPI 的有价值的核心。