Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response.
Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response.
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DOI：
10.1002/anie.201607338
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发表时间：
2016-11
影响因子：
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通讯作者：
F. Mandl;Volker C. Kirsch;I. Ugur;E. Kunold;Jan Vomacka;C. Fetzer;S. Schneider;K. Richter;T. Fuchs;I. Antes;S. Sieber
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文献类型：
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作者：
F. Mandl;Volker C. Kirsch;I. Ugur;E. Kunold;Jan Vomacka;C. Fetzer;S. Schneider;K. Richter;T. Fuchs;I. Antes;S. Sieber
革兰氏阴性细菌由于其不可渗透的细胞膜和小分子的摄取受到限制，对于抗菌药物的发现来说是一项具有挑战性的任务。我们在此描述了天然产物衍生的环氧环己烯酮的合成，并探讨了它们对几种病原菌的抗生素活性。鉴定出一种具有抗鼠伤寒沙门氏菌活性的化合物，并通过定量化学蛋白质组学阐明了目标酶。重要的是，两种蛋白质命中与细菌应激反应有关，并且相应的测定显示在化合物处理后对活性氧的敏感性升高。这些靶标的综合抑制为抗菌活性提供了理论依据，并强调环氧环己烯酮作为天然产物支架，具有杀死革兰氏阴性沙门氏菌的合适特性。
Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram-negative Salmonella.