Abstract
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−1. 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.
Highlights
Marine gastropod mollusks that are defended by thick shells harbor diverse culturable bacteria, many of which produce biologically active compounds [1,2,3,4]
When methicillin-resistant Staphylococcus aureus (MRSA) (ATCC® 43300TM) was treated simultaneously with 7,8-dideoxygriseorhodin C and oxacillin, a more potent antimicrobial activity was observed compared with the single-drug treatments
The synergistic activity of 7,8-dideoxygriseorhodin C with oxacillin was determined by performing the antimicrobial microdilution broth assay as described above
Summary
Marine gastropod mollusks that are defended by thick shells harbor diverse culturable bacteria, many of which produce biologically active compounds [1,2,3,4]. Our continuing efforts to screen extracts from mollusk-associated bacteria against methicillin-resistant Staphylococcus aureus (MRSA) led us to. We have begun to test compounds isolated from marine mollusk-associated bacteria that show anti-MRSA activity in combination with known antibiotics to identify potential synergistic interactions. When MRSA (ATCC® 43300TM) was treated simultaneously with 7,8-dideoxygriseorhodin C and oxacillin, a more potent antimicrobial activity was observed compared with the single-drug treatments This indicates possible synergistic activity, which may translate to a more rapid clearance of infection, shorter course of antibiotic therapy, and a reduction of dose-related toxicity [13]. All carbon chemical shift signals were assigned, and the stereochemistry was determined to be 6S,6aS by using a combination of spectroscopic and computational methods
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