Abstract
Rising drug resistance limits the treatment options infected by methicillin-resistant Staphylococcus aureus (MRSA). A promising solution for overcoming the resistance of MRSA is to inhibit the penicillin-binding protein 2a (PBP2a). A novel terpene-polyketide hybrid meroterpenoid, aspermerodione (1), characterized by an unusual 2,6-dioxabicyclo[2.2.1]heptane core skeleton, and a new heptacyclic analogue, andiconin C (2), were isolated and identified from the liquid cultures of endophytic fungus Aspergillus sp. TJ23. The structures and their absolute configurations of all chiral centers were elucidated via extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations and determined via single-crystal X-ray diffraction analysis. Aspemerodione (1) was found to be a potential inhibitor of PBP2a, and work synergistically with the β-lactam antibiotics oxacillin and piperacillin against MRSA.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, and it represents a major public health problem[1]
After repeated recrystallization by various solvent systems, 2 furnished a high-quality crystal in a mixture of CHCl3–MeOH (7:3) at room temperature, which was successfully subjected to single-crystal X-ray diffraction using Cu Kα radiation (Fig. 6) with a Flack parameter of –0.03(5) (CCDC 1554256)[17], which enabled us to confirm its absolute configuration as 1S,2′R,3′S,5R,5′S,8S,9R,10S,11S (Fig. 1)
Our research demonstrates that aspermerodione (1) has anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and based on the observation of transmission electron microscopy (TEM), the anti-MRSA activity of 1 might be tightly related to its effect of damaging bacterial cell wall and/or membrane
Summary
After repeated recrystallization by various solvent systems, 2 furnished a high-quality crystal in a mixture of CHCl3–MeOH (7:3) at room temperature, which was successfully subjected to single-crystal X-ray diffraction using Cu Kα radiation (Fig. 6) with a Flack parameter of –0.03(5) (CCDC 1554256)[17], which enabled us to confirm its absolute configuration as 1S,2′R,3′S,5R,5′S,8S,9R,10S,11S (Fig. 1) To further support this deduction, the calculated ECD spectrum of 1S,2′R,3′S,5R,5′S,8S,9R,10S-2 was determined at the B3LYP/6–31 G(d,p) level and showed an excellent coincidence with the experimental ECD curve (Fig. 7), which undoubtedly corroborated its absolute structure. Andiconin could be transformed to 2 via a series of reactions including reduction, dehydration, oxidation, Michael addition, and keto-enol tautomerism
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