Structure-based isolation of bioactive Strychnos indole and new aporphine alkaloids from traditional Chinese medicine as anti-MRSA candidates: computational screening and antibacterial evaluation

Traditional Chinese medicine (TCM) harbours structurally diverse alkaloids with potential against methicillin-resistant Staphylococcus aureus (MRSA). Here, 983 alkaloids from 82 TCM species were screened by multi-target molecular docking against four MRSA resistance proteins, among them IleRS, PBP2a, DNA gyrase, and PBP2a-penicillin G acyl-enzyme, prioritising 50 top-ranked candidates (ΔG ≤ −7 kcal/mol). Bisindole strychnines from Strychnos nux-vomica were top-ranked leads, confirmed by 100 ns molecular dynamics simulations. Feature-based molecular networking (FBMN) via GNPS2 directed bioassay-guided isolation from S. nux-vomica and Aristolochia contorta, yielding 24 alkaloids including two new aporphines, 2,4-dihydroxy-1-methoxynoraporphine (N2) and 2,4-dihydroxy-1-methoxyaporphine (N3), fully characterised by 1D/2D NMR and HRESIMS. Antibacterial evaluation against S. aureus ATCC6538 and MRSA ATCC BAA-1717 revealed the lipophilic noraporphines asimilobine (N4) and 1,2-dimethoxynoraporphine (N5) as the most potent compounds, with MIC50 values against MRSA of 16.5 ± 7.1 and 11.3 ± 9.8 µg/mL, respectively (191 µg/mL and inactive, respectively, against MSSA). Structure-activity analysis identified lipophilic methoxylated noraporphine scaffolds and the bisindole strychnine skeleton as key pharmacophoric features, identifying these alkaloids as candidate anti-MRSA leads warranting further in vivo validation.