Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, 84112, USA.
The Marine Science Institute, University of the Philippines Diliman, Quezon City, 1101, Philippines.
J Antibiot (Tokyo). 2020 May;73(5):290-298. doi: 10.1038/s41429-019-0275-8. Epub 2020 Jan 28.
The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the β-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 μg ml. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.
抗生素耐药性的出现不仅需要鉴定具有抗菌特性的新化合物，还需要新的策略和联合疗法来规避这一日益严重的问题。在这里，我们报告了β-内酰胺抗生素苯唑西林与 7,8-二脱氧灰黄霉素 C 体外联合对耐甲氧西林金黄色葡萄球菌（MRSA）的协同活性。从海洋腹足类组织匀浆中培养的一株链霉菌中分离出 7,8-二脱氧灰黄霉素 C，这是从海洋贝类相关细菌中鉴定抗生素的持续努力的结果。尽管 7,8-二脱氧灰黄霉素 C 在文献中有很长的历史，但它的绝对构型从未被报道过。通过比较实测和计算的 ECD 光谱，解决了螺缩酮碳 C6 的构型问题，2D ROESY NMR 光谱确定了绝对构型为 6s,6aS。该化合物对革兰氏阳性菌包括 MRSA 和屎肠球菌具有选择性，MIC 范围为 0.125-0.5μg/ml。此外，该化合物与苯唑西林协同作用对 MRSA 的抗菌微量稀释和时间杀伤试验中得到了观察。该化合物与苯唑西林同时治疗导致 MIC 约降低十倍，组合指数<0.5，表明具有协同抗 MRSA 活性。
