Biotechnology Group, Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Applied Organic Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India.
Bioorg Med Chem. 2022 Jan 15;54:116580. doi: 10.1016/j.bmc.2021.116580. Epub 2021 Dec 17.
Staphylococcus aureus is an emerging human pathogen that has become difficult to treat due to its high resistance against wide range of drugs. Emergence of drug resistant isolates has further convoluted the treatment process. Among different resistance mechanisms, efflux pump proteins play a central role and has made itself a direct approach for therapeutic exploration. To demarcate the role of dihydroquinazoline analogues as NorA efflux pump inhibitor in S. aureus1199B (NorA over producing) strain total seventeen analogues were synthesized and tested for their modulatory effects on norfloxacin and Etbr resistance. Further accumulation assays, bacterial time kill kinetics, cytotoxicity assay were also carried out. The intracellular killing ability of analogues, as EPI was determined using THP-1 monocytes. The binding interaction of analogues with NorA was also predicted. Dihydroquinazoline analogues notably reduced the MIC of norfloxacin and Etbr in S. aureus1199B. In addition to their very low toxicity, they showed high Etbr and norfloxacin accumulation respectively. Further effective over time log reduction in bacterial kill kinetics in presence of these analogues confirmed their role as NorA efflux pump inhibitor. FESEM analysis clearly depicted their effect on the cell surface morphology owing to its lyses. The most significant finding of this study was the ability of analogues to significantly reduce the intracellular S. aureus1199B in human THP-1 monocytes in presence of norfloxacin. Our study has shown for the first time the possibility of developing the dihydroquinazoline analogues as NorA efflux pump inhibitors for S. aureus and control its infection.
金黄色葡萄球菌是一种新兴的人类病原体，由于其对广泛的药物具有高度耐药性，因此变得难以治疗。耐药分离株的出现进一步使治疗过程复杂化。在不同的耐药机制中，外排泵蛋白起着核心作用，并使其成为治疗探索的直接方法。为了确定二氢喹唑啉类似物作为 NorA 外排泵抑制剂在金黄色葡萄球菌 1199B（NorA 过度产生）菌株中的作用，合成了 17 种类似物，并测试了它们对诺氟沙星和 Etbr 耐药性的调节作用。还进行了进一步的积累测定、细菌时间杀伤动力学和细胞毒性测定。使用 THP-1 单核细胞测定类似物作为 EPI 的细胞内杀伤能力。还预测了类似物与 NorA 的结合相互作用。二氢喹唑啉类似物显著降低了金黄色葡萄球菌 1199B 中诺氟沙星和 Etbr 的 MIC。除了它们的毒性非常低之外，它们还分别显示出高 Etbr 和诺氟沙星积累。在存在这些类似物的情况下，细菌杀伤动力学的有效时间对数减少进一步证实了它们作为 NorA 外排泵抑制剂的作用。FESEM 分析清楚地描绘了它们对细胞表面形态的影响，因为它们的裂解。这项研究的最重要发现是，在存在诺氟沙星的情况下，类似物能够显著降低人 THP-1 单核细胞中金黄色葡萄球菌 1199B 的细胞内含量。我们的研究首次表明，开发二氢喹唑啉类似物作为 NorA 外排泵抑制剂用于金黄色葡萄球菌并控制其感染是可能的。
