Antibacterial diphenyl ether derivatives from mangrove-derived fungus Aspergillus versicolor 21041517

Three new diphenyl ethers diorcinols P-Q (1-2), and gibellulin E (3), together with one new sesquiterpene isoversiol H (4), as well as six known diphenyl ethers (5-10) were obtained from the mangrove-derived fungus Aspergillus versicolor 21041517. Comprehensive spectroscopic techniques, ECD calculations, X-ray diffraction analyses, and modified Mosher's method were used to confirm the planner structures and absolute configurations of the new compounds. The diphenyl ethers 1, 5 and 6 exhibited inhibitory activity against three tested pathogenic bacteria. 20 diphenyl ether derivatives (5a1-5j2) were designed and semisynthesized to improve the antibacterial activity of diphenyl ethers. In particular, compound 5a1 showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), with the MIC value of 3.13 μg/mL. Preliminary antimicrobial mechanism investigations of 5a1 were performed. Treatment with 5a1 resulted in the leakage of the AKP, a decrease in intracellular ATP concentration, and a reduction in soluble protein content. Scanning electron microscopy demonstrated that 5a1 can damage the cell membrane of MRSA. Transcriptome assay revealed that 5a1 may target cellular energy metabolism. This study offers valuable insights that contribute to development of novel anti-MRSA agents, and providing potential strategies for addressing antibiotic.