Mycobacterium avium is a difficult-to-treat pathogen able to quickly develop drug resistance. Like for other microbial species, overexpression of efflux pumps is one of the main mechanisms in developing multidrug resistance. Although the use of efflux pumps inhibitors (EPIs) represents a promising strategy to reverse resistance, to date few M. avium EPIs are known. Recently, we showed that in-house 2-phenylquinoline S. aureus NorA EPIs exhibited also a good activity against M. avium efflux pumps. Herein, we report a series of 3-phenylquinolones designed by modifying the isoflavone biochanin A, a natural EPI of the related M. smegmatis, taking into account some important SAR information obtained around the 2-phenylquinoline NorA EPIs. The 3-phenylquinolones inhibited M. avium efflux pumps with derivatives 1e and 1g that displayed the highest synergistic activity against all the strains considered in the study, bringing down (from 4- to 128-fold reduction) the MIC values of macrolides and fluoroquinolones.

鸟分枝杆菌是一种难以治疗的病原体，能够迅速产生耐药性。像其他微生物一样，外排泵的过表达是产生多药耐药性的主要机制之一。尽管外排泵抑制剂（EPI）的使用代表了逆转耐药性的一种有前途的策略，但迄今为止，很少知道鸟分枝杆菌的EPI。最近，我们表明内部的2-苯基喹啉金黄色葡萄球菌NorA EPIs还表现出良好的抗鸟分枝杆菌外排泵的活性。在此，我们报告了一系列通过修饰异黄酮生物素A（相关耻垢分枝杆菌的天然EPI）而设计的一系列3-苯基喹诺酮类药物。考虑到在2-苯基喹啉NorA EPI周围获得的一些重要SAR信息。3-苯基喹诺酮类药物对衍生的1e和1g抑制鸟分枝杆菌外排泵，对研究中考虑的所有菌株均显示出最高的协同活性，从而降低了大环内酯类和氟喹诺酮类药物的MIC值（从4-倍降低至128倍）。