18-beta-glycyrrhetinic acid and methicillin resistant Staphylococcus aureus : from lytic activity to reduced pathogenesis

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is Gram-positive pathogen known to cause severe disease in humans. MRSA's resistance to the beta-lactam class of antibiotics makes it an increasing healthcare concern. Over the last two decades there has been a rise in the incidence of community-associated MRSA, specifically pulsed-field gel electrophoresis type USA300 (known to cause severe skin and soft tissue infections). The development of drug therapies against MRSA infections that do not induce resistance and have efficacy against MRSA is a pressing matter. In this study, we investigate the potential of two components in licorice extracts, Glycyrrhizic acid (GA) and 18-beta-Glycyrrhetinic acid (GRA), as effective antimicrobials against MRSA. Using in vitro survival assays, we determined that GRA is directly bactericidal to MRSA. Using a murine model of skin and soft tissue infection, we discovered that topical treatment with GRA reduced severity of MRSA skin and soft tissue infections more rapidly than treatment with GA or a control. The increase in infection clearance was not due to a reduction in bacterial burden, but results indicate that GRA may decrease severity of the infection via an effect on the immune system. Treatment of an MRSA skin infection with GRA reduced expression of KC and G-CSF. To further investigate how GRA treatment led to a more rapid clearance of infection, we analyzed the expression of five S. aureus virulence genes (saeR, hla, RNAIII transcript, mecA, and sbi) after treatment with GRA or GA. GRA rapidly down-regulated four of the five virulence genes in vitro and all five virulence genes in vivo in the skin infection model. The data presented here shows that GRA is bactericidal, assists in decreasing the severity of MRSA infection via down-regulation of virulence genes, and can induce an altered immune response in the host.