Targeting MCR-3 and Membrane Biosynthesis: Mechanistic Insights into Pterostilbene-Polymyxin Synergy

This study confirmed that pterostilbene can enhance the antibacterial activity of polymyxin against mcr - 3 - positive Escherichia coli through transcriptomic regulation. Transcriptomic analysis showed that pterostilbene significantly down - regulated genes related to fatty acid biosynthesis and central carbon metabolism (such as fabH, accA), and up - regulated genes in the fatty acid degradation pathway (such as fadD, ech). This metabolic reprogramming led to impaired bacterial membrane integrity (verified by electron microscopy and membrane permeability experiments). The addition of exogenous phospholipids could weaken the synergistic effect, suggesting that lipid metabolic disorder is a key mediator of membrane stability disruption. Combining the results of molecular docking and site - directed mutagenesis, pterostilbene can also directly target the catalytic residues H380 and E111 of the MCR - 3 enzyme to inhibit its phosphoethanolamine transferase activity. In conclusion, transcriptome - driven metabolic intervention and direct inhibition of the MCR - 3 enzyme together constitute the core mechanism by which pterostilbene reverses mcr - mediated polymyxin resistance.