Platanosides from Platanus x acerifolia: New molecules, SAR, and target validation of a strong lead for drug-resistant bacterial infections and the associated sepsis

• Main Authors: Wu, Xi-Ying, Zhao, Ze-Yu, Osman, Ezzat E. A., Wang, Xiao-Juan, Choo, Yeun-Mun, Benjamin, Menny M., Xiong, Juan, Hamann, Mark T., Luo, Cheng, Hu, Jin-Feng
• Format: Article
• Published: Elsevier 2024
• Subjects: QD Chemistry; R Medicine (General); RM Therapeutics. Pharmacology; RS Pharmacy and materia medica
• Online Access: http://eprints.um.edu.my/45804/; https://doi.org/10.1016/j.bioorg.2024.107103
• Institution: Universiti Malaya

Three undescribed (1-3) and nine known (4-12) platanosides were isolated and characterized from a bioactive extract of the May leaves of Platanus x acerifolia that initially showed inhibition against Staphylococcus aureus. Targeted compound mining was guided by an LC-MS/MS-based molecular ion networking (MoIN) strategy combined with conventional isolation procedures from a unique geographic location. The novel structures were mainly determined by 2D NMR and computational (NMR/ECD calculations) methods. Compound 1 is a rare acylated kaempferol rhamnoside possessing a truxinate unit. 6 (Z,E-platanoside) and 7 (E,E-platanoside) were confirmed to have remarkable inhibitory effects against both methicillin-resistant S. aureus (MIC: <= 16 mu g/mL) and glycopeptide-resistant Enterococcus faecium (MIC: <= 1 mu g/mL). These platanosides were subjected to docking analyses against FabI (enoyl-ACP reductase) and PBP1/2 (penicillin binding protein), both of which are pivotal enzymes governing bacterial growth but not found in the human host. The results showed that 6 and 7 displayed superior binding affinities towards FabI and PBP2. Moreover, surface plasmon resonance studies on the interaction of 1/7 and FabI revealed that 7 has a higher affinity (KD = 1.72 mu M), which further supports the above in vitro data and is thus expected to be a novel anti-antibacterial drug lead.