Plant Natural Flavonoids Against Multidrug Resistant Pathogens

The increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens accelerate the desires for new antibiotics. Natural products dominate the preferred chemical scaffolds for the discovery of antibacterial agents. Here, the potential of natural flavonoids from plants against MDR bacteria, is demonstrated. Structure-activity relationship analysis shows the prenylation modulates the activity of flavonoids and obtains two compounds, alpha-mangostin (AMG) and isobavachalcone (IBC). AMG and IBC not only display rapid bactericidal activity against Gram-positive bacteria, but also restore the susceptibility of colistin against Gram-negative pathogens. Mechanistic studies generally show such compounds bind to the phospholipids of bacterial membrane, and result in the dissipation of proton motive force and metabolic perturbations, through distinctive modes of action. The efficacy of AMG and IBC in four models associated with infection or contamination, is demonstrated. These results suggest that natural products of plants may be a promising and underappreciated reservoir to circumvent the existing antibiotic resistance.

Automated summary

This study demonstrates the potential of natural flavonoids from plants against multidrug resistant bacteria, with a focus on the structure-activity relationship analysis of two compounds, alpha-mangostin and isobavachalcone. These compounds show rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, and mechanism studies suggest they target bacterial membrane phospholipids. The efficacy of these natural products in infection or contamination models highlights them as a promising and underappreciated resource for combating antibiotic resistance.