{Reference Type}: Journal Article
{Title}: Discovery of Gambogic acid as an antibacterial adjuvant against vancomycin-resistant enterococci in vitro and in vivo.
{Author}: Pang J;Guo X;Zhang Z;Guo W;Yuan M;Li Z;Lu X;Wang Y;You X;
{Journal}: Phytomedicine
{Volume}: 128
{Issue}: 0
{Year}: 2024 Jun 1
{Factor}: 6.656
{DOI}: 10.1016/j.phymed.2024.155400
{Abstract}: <B>BACKGROUND: </B>The emergence and spread of vancomycin-resistant enterococci (VRE) have posed a significant challenge to clinical treatment, underscoring the need to develop novel strategies. As therapeutic options for VRE are limited, discovering vancomycin enhancer is a feasible way of combating VRE. Gambogic acid (GA) is a natural product derived from the resin of Garcinia hanburyi Hook.f. (Clusiaceae), which possesses antibacterial activity.<BR><B>OBJECTIVE: </B>This study aimed to investigate the potential of GA as an adjuvant to restore the susceptibility of VRE to vancomycin.<BR><B>METHODS: </B>In vitro antibacterial and synergistic activities were evaluated against vancomycin-susceptible and resistant strains by the broth microdilution method for the Minimal Inhibitory Concentrations (MICs) determination, and checkerboard assay and time-kill curve analysis for synergy evaluation. In vivo study was conducted on a mouse multi-organ infection model. The underlying antibacterial mechanism of GA was also explored.<BR><B>RESULTS: </B>GA showed a potent in vitro activity against all tested strains, with MICs ranging from 2 to 4 μg/ml. The combination of GA and vancomycin exhibited a synergistic effect against 18 out of 23 tested VRE strains, with a median fractional inhibitory concentration index (FICI) of 0.254, and demonstrated a synergistic effect in the time-kill assay. The combination therapy exhibited a significant reduction in tissue bacterial load compared with either compound used alone. GA strongly binds to the ParE subunit of topoisomerase IV, a bacterial type II DNA topoisomerase, and suppresses its activity.<BR><B>CONCLUSIONS: </B>The study suggests that GA has a significant antibacterial activity against enterococci, and sub-MIC concentrations of GA can restore the activity of vancomycin against VRE in vitro and in vivo. These findings indicate that GA has the potential to be a new antibacterial adjuvant to vancomycin in the treatment of infections caused by VRE.