Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H₂O₂ killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.

通过阻止类胡萝卜素色素的生物合成，抑制细菌免受宿主氧化剂的杀伤作用，抑制金黄色葡萄球菌的二氢番茄红素去饱和酶（CrtN）可以作为解决棘手的抗生素耐药性的另一种方法。在这项研究中，我们设计和合成了针对CrtN的胡椒基骨架支架的44种衍生物，并对其结构活性关系（SARs）进行了广泛研究，以发现与第一类CrtN抑制剂苯并环烷烃相比具有更有效的hERG安全性的21b的发现。导数2。除了对野生型金黄色葡萄球菌具有出色的色素抑制活性外，21b还显示出对四种有色MRSA菌株的出色的色素抑制作用。另外，H ₂ O ₂杀灭和人全血杀灭测定证明21b可以使金黄色葡萄球菌在氧化应激条件下被杀死。值得注意的是，在体内进行的鼠类研究验证了21b对有色金黄色葡萄球菌Newman，万古霉素中间体金黄色葡萄球菌Mu50和耐利奈唑胺的金黄色葡萄球菌NRS271的功效。