Synergistic effects of new lactone polyketides from an endophytic fungus Phomopsis sp. XP-8 with antibiotics

Six new polyketides, including three naphthalene-types (1-3) and three γ-lactones-types (4-6), along with 14 known polyketides (7-20), were isolated from a pathogen endophytic fungus Phomopsis sp. XP-8 of Eucommia ulmoides Oliver. Their structures were elucidated by spectrometric analysis using MS and NMR data. The absolute configurations were established using statistical comparative analysis of the experimental ECD data, in conjunction with quantum mechanical calculations. All the compounds and crude extracts were evaluated for their antibacterial activity. Compounds 2, 3, 6, 7, 8, and 10 exhibited moderate inhibition on three gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis, and Bacillus thuringiensis. Synergistic antibacterial interaction experiments showed that compounds 1, 2, 3, 6, 7, 8, and 19 with antibiotics can greatly enhance the inhibition rate against bacteria. The target screening and molecular docking of these compounds were also carried out, with further verification of molecular dynamics, revealing that the compounds exert antibacterial activity by targeting both the Fur-regulated basic protein (FbpB) and drug resistance protein D (EmrD), exhibiting synergy with antibiotics by inhibiting the DNA polymerase III β-subunit resulting in enhanced efficacy.