Multidrug efflux is a major contributor to antibiotic resistance in Gram-negative bacterial pathogens. Inhibition of multidrug efflux pumps is a promising approach for reviving the efficacy of existing antibiotics. Previously, inhibitors targeting both the efflux transporter AcrB and the membrane fusion protein AcrA in the Escherichia coli AcrAB-TolC efflux pump were identified. Here we use existing physicochemical property guidelines to generate a filtered library of compounds for computational docking. We then experimentally test the top candidate coumpounds using in vitro binding assays and in vivo potentiation assays in bacterial strains with controllable permeability barriers. We thus identify a new class of inhibitors of E. coli AcrAB-TolC. Six molecules with a shared scaffold were found to potentiate the antimicrobial activity of erythromycin and novobiocin in hyperporinated E. coli cells. Importantly, these six molecules were also active in wild-type strains of both Acinetobacter baumannii and Klebsiella pneumoniae, potentiating the activity of erythromycin and novobiocin up to 8-fold.

中文翻译：

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发现具有新型化学支架的多药外排泵抑制剂。

多药外排是革兰氏阴性细菌病原体对抗生素耐药性的主要贡献者。抑制多药外排泵是恢复现有抗生素功效的一种有前途的方法。以前，已鉴定了针对大肠杆菌AcrAB-TolC外排泵中外排转运蛋白AcrB和膜融合蛋白AcrA的抑制剂。在这里，我们使用现有的理化性质指南来生成用于计算对接的过滤后的化合物库。然后，我们在具有可控渗透性屏障的细菌菌株中使用体外结合测定法和体内增强测定法，对顶级候选化合物进行了实验性测试。因此，我们确定了一类新的大肠杆菌AcrAB-TolC抑制剂。发现具有共享支架的六个分子增强了超孔化大肠杆菌细胞中的红霉素和新霉素的抗菌活性。重要的是，这六个分子在鲍曼不动杆菌和肺炎克雷伯菌的野生型菌株中也有活性，可将红霉素和新霉素的活性增强至8倍。