Rubiginoids A-N, phytocannabinoid-like meroterpenoids with diverse ring systems from Rhododendron rubiginosum

Methicillin-resistant Staphylococcus aureus (MRSA) has posed a serious global threat over recent decades due to its multidrug-resistant nature. Chemical examination of the leaves of Rhododendron rubiginosum afforded sixteen PLMs (phytocannabinoid-like meroterpenoids, 1-16), fourteen of which (1-14) are new isolates, designated as rubiginoids A-N. Comprehensive analyses of spectral data (NMR and HRESIMS), along with electronic circular dichroism (ECD) calculations, NMR computations, and DP4+ probability analyses, enabled the elucidation of their structures and absolute configurations. Notably, rubiginoid A features an unprecedented 6/6/5 heterocyclic framework, while rubiginoids B and C contain a rare 6/6/6 ring system. Proposed biosynthetic pathways of rubiginoids A-C suggest that these unique PLMs could originate from a resorcinol moiety and sesquiterpenoid precursors through key cyclization, oxidation, and addition steps. Among the isolates, PLM 15 exhibited the most potential antibacterial activity against MRSA, with both minimum inhibitory concentration and minimum bactericidal concentration values of 1 μg/mL. Mechanism investigations demonstrated that compound 15 exerts rapid bactericidal effects by disrupting MRSA cell membranes. Furthermore, molecular docking analysis indicated potential interactions of 15 with the biofilm-associated protein Bap. Collectively, these findings highlight rubiginoids as promising antibacterial candidates with potential anti-biofilm properties for combating MRSA infections.