Lu Wen-Jung, Lian Yu-Wei, Chang Chun-Ju, Lin Hsuan-Ju, Huang Chian-Yun, Hsu Pang-Hung, Lin Hong-Ting
Department of Food Science, National Taiwan Ocean University, Keelung 202, Taiwan.
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Antibiotics (Basel). 2024 Jul 5;13(7):628. doi: 10.3390/antibiotics13070628.
Drug-resistant efflux pumps play a crucial role in bacterial antibiotic resistance. In this study, potential efflux pump inhibitors (EPIs) with a diphenylmethane scaffold were screened and evaluated against drug-resistant . Twenty-four compounds were docked against the drug-binding site of multidrug transporter AcrB, and 2,2-diphenylethanol (DPE), di--tolyl-methanol (DPT), and 4-(benzylphenyl) acetonitrile (BPA) were screened for their highest binding free energy. The modulation assay was further used for EPI evaluation, revealing that DPE, DPT, and BPA could reduce the drug IC value in strains overexpressing AcrB, indicating their modulation activity. Only DPE and BPA enhanced intracellular dye accumulation and inhibited the efflux of ethidium bromide and erythromycin. In addition, DPE and BPA showed an elevated post-antibiotic effect on drug-resistant , and they did not damage the permeability of the bacterial outer membrane. The cell toxicity test showed that DPE and BPA had limited human-cell toxicity. Therefore, DPE and BPA demonstrate efflux pump inhibitory activity, and they should be further explored as potential enhancers to improve the effectiveness of existing antibiotics against drug-resistant .
耐药性外排泵在细菌抗生素耐药性中起着关键作用。在本研究中，筛选并评估了具有二苯甲烷支架的潜在外排泵抑制剂（EPI）对耐药菌的作用。24种化合物与多药转运蛋白AcrB的药物结合位点进行对接，筛选出2,2 - 二苯基乙醇（DPE）、二 - 对甲苯基甲醇（DPT）和4 - （苄基苯基）乙腈（BPA），它们具有最高的结合自由能。进一步使用调节试验评估EPI，结果表明DPE、DPT和BPA可降低过表达AcrB菌株中的药物IC值，表明它们具有调节活性。只有DPE和BPA增强了细胞内染料积累，并抑制了溴化乙锭和红霉素的外排。此外，DPE和BPA对耐药菌显示出增强的抗生素后效应，并且它们不会破坏细菌外膜的通透性。细胞毒性试验表明，DPE和BPA对人类细胞的毒性有限。因此，DPE和BPA表现出外排泵抑制活性，应进一步探索它们作为潜在增强剂，以提高现有抗生素对耐药菌的有效性。
