Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target that is not addressed by any antibiotic in the market. Since the ECF module is crucial for the vitamin transport mechanism, the prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects.

中文翻译：

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针对能量耦合因子转运蛋白的小分子叶酸摄取抑制剂的结构导向优化

在这里，我们报告了一类针对能量耦合因子 (ECF) 转运蛋白的有效取代脲基噻吩，这是市场上任何抗生素都没有解决的未开发目标。由于 ECF 模块对维生素转运机制至关重要，因此阻止底物吸收最终会导致细胞死亡。通过利用我们内部库的虚拟和功能全细胞筛选相结合，可以有效抑制膜结合蛋白介导的叶酸摄取。我们的命中基于结构的优化产生了低微摩尔抑制剂，其中最活跃的化合物还显示出针对一组临床相关的革兰氏阳性病原体的有效抗菌活性，而没有显着的细胞毒性作用。