Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy.
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy , Jagiellonian University-Medical College , ul. Medyczna 9 , 31-688 Cracow , Poland.
J Med Chem. 2018 Sep 13;61(17):7827-7848. doi: 10.1021/acs.jmedchem.8b00791. Epub 2018 Aug 17.
Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitorial drug concentrations. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR. Given our experience in developing Staphylococcus aureus NorA EPIs, in this work, starting from the 2-phenylquinoline hit 1, we planned the introduction of methoxy groups on the basis of their presence in known NorA EPIs. Among the 35 different synthesized derivatives, compounds 3b and 7d exhibited the best NorA inhibition activity by restoring at very low concentrations ciprofloxacin MICs against resistant S. aureus strains. Interestingly, both compounds displayed EPI activities at nontoxic concentrations for human cells as well as highlighted promising results by preliminary pharmacokinetic studies.
抗菌药物耐药性（AMR）是药物发现领域的一个热门话题。除了鉴定新的抗生素外，使用非抗生素分子来阻断耐药机制是一种强有力的替代方法。细菌外排泵通过允许细菌在亚抑菌药物浓度下生长，在 AMR 发展的早期阶段发挥作用。因此，外排泵抑制剂（EPIs）为对抗 AMR 提供了一个很好的机会。鉴于我们在开发金黄色葡萄球菌 NorA EPIs 方面的经验，在这项工作中，我们从 2-苯基喹啉起始物 1 开始，根据已知 NorA EPIs 中存在的甲氧基基团，计划引入甲氧基。在所合成的 35 种不同衍生物中，化合物 3b 和 7d 表现出最好的 NorA 抑制活性，以非常低的浓度恢复对耐药金黄色葡萄球菌菌株的环丙沙星 MIC。有趣的是，这两种化合物都以非毒性浓度显示出对人细胞的 EPI 活性，并且通过初步药代动力学研究显示出有希望的结果。
