Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.
Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.
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DOI：
10.1016/j.ejmech.2017.12.090
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发表时间：
2018-02
影响因子：
6.7
通讯作者：
Hanwen Wei;Fei Mao;Shuaishuai Ni;Feifei Chen;Baoli Li;X. Qiu;Linghao Hu;Manjiong Wang;Xinyu Zheng;Jin Zhu;L. Lan;Jian Li
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文献类型：
--
作者：
Hanwen Wei;Fei Mao;Shuaishuai Ni;Feifei Chen;Baoli Li;X. Qiu;Linghao Hu;Manjiong Wang;Xinyu Zheng;Jin Zhu;L. Lan;Jian Li
抑制金黄色葡萄球菌二脱辅八氢番茄红素去饱和酶（CrtN）可以作为一种替代方法，通过阻断类胡萝卜素色素的生物合成来解决棘手的抗生素抗性，类胡萝卜素色素使细菌免受宿主氧化剂的杀伤。在这项研究中，我们设计并合成了44个具有胡椒基骨架的衍生物，并对结构-活性关系（SAR）进行了广泛的研究，以发现21 b与第一类CrtN抑制剂苯并环烷烃衍生物2相比具有更有效的功效和更好的hERG安全性。除了对野生型金黄色葡萄球菌具有优异的色素抑制活性外，21 b还对四种着色的MRSA菌株具有优异的色素抑制活性。此外，H2 O2杀伤和人全血杀伤试验证明21 b可使金葡菌在氧化应激条件下敏感而被杀死。值得注意的是，小鼠体内研究验证了21 b对着色金黄色葡萄球菌Newman、万古霉素中间体金黄色葡萄球菌Mu 50和利奈唑胺耐药金黄色葡萄球菌NRS 271的疗效。
Inhibition ofS. aureusdiapophytoene 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 of21bwith potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative2. Except the excellent pigment inhibitory activity against wild-typeS. aureus,21balso showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2killing and human whole blood killing assays proved21bcould sensitizeS. aureusto be killed under oxidative stress conditions. Notably, the murine studyin vivovalidated the efficacy of21bagainst pigmentedS. aureusNewman, vancomycin-intermediateS. aureusMu50 and linezolid-resistantS. aureusNRS271.