Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens University Graz , Universitätsplatz 4, 8010 Graz, Austria.
J Nat Prod. 2012 Jul 27;75(7):1393-9. doi: 10.1021/np300375t. Epub 2012 Jul 13.
In order to identify new putative efflux pump inhibitors that represent an appropriate target in antimycobacterial chemotherapy, nine paradol- and gingerol-related compounds (1-9) isolated from the seeds of Aframomum melegueta were assessed for their potential to inhibit ethidium bromide (EtBr) efflux in a Mycobacterium smegmatis model. Five of the compounds from A. melegueta and NMR spectroscopic data of the diketone 6-gingerdione (2) and its enolic tautomers, methyl-6-gingerol (5) and rac-6-dihydroparadol (7), are presented herein for the first time. After determination of their antimycobacterial activities and modulatory effects on the MIC of antibiotics as well as their synergistic effects in combination with antibiotics against M. smegmatis mc(2) 155, their impact on EtBr accumulation and efflux was evaluated using a microtiter plate-based fluorometric assay. The compounds exhibited moderate to weak antimycobacterial activities, and the best modulators induced a 4- to 16-fold decrease of the MICs of EtBr and rifampicin as well as a reduction of the MIC of isoniazid with fractional inhibitory concentration index values indicating synergistic activities in some cases. 6-Paradol (3), 8-gingerol (6), and rac-6-dihydroparadol (7) were the most potent EtBr efflux inhibitors in M. smegmatis mc(2) 155, displaying EtBr efflux inhibiting activities comparable to reference inhibitors.
为了鉴定新的潜在外排泵抑制剂，作为抗分枝杆菌化学疗法的合适靶点，从 Aframomum melegueta 种子中分离得到的 9 种伪多醇和姜酚相关化合物（1-9），评估了它们在 Mycobacterium smegmatis 模型中抑制溴化乙锭（EtBr）外排的潜力。本文首次报道了来自 A. melegueta 的 5 种化合物以及二酮 6-姜二酮（2）及其烯醇互变异构体、甲基-6-姜酚（5）和 rac-6-二氢伪多醇（7）的 NMR 光谱数据。在确定了它们的抗分枝杆菌活性以及对抗生素 MIC 的调节作用和与抗生素联合使用对 M. smegmatis mc(2) 155 的协同作用后，使用基于微量滴定板的荧光测定法评估了它们对 EtBr 积累和外排的影响。这些化合物表现出中等至弱的抗分枝杆菌活性，最佳调节剂使 EtBr 和利福平的 MIC 降低了 4 至 16 倍，异烟肼的 MIC 降低，部分情况下的分数抑菌浓度指数值表明具有协同活性。6-伪多醇（3）、8-姜酚（6）和 rac-6-二氢伪多醇（7）是 M. smegmatis mc(2) 155 中最强的 EtBr 外排抑制剂，显示出与参考抑制剂相当的 EtBr 外排抑制活性。
