Hypericin enhances -lactam antibiotics activity by inhibiting expression in methicillin-resistant

ABSTRACT

Bacteremia is a life-threating syndrome often caused by methicillin-resistant (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and -lactam antibiotic resistance in . Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on -lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of -lactam antibiotics (.., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced expression, and subsequently decreased and virulence-related regulators (.., ) and genes (.., and ) expression in the studied MRSA strain. Importantly, the synergistic effect of hypericin with -lactam antibiotic (.., oxacillin) translated into therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of -lactam resistance against MRSA through inhibition, and may allow us to repurpose the use of -lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (.., oxacillin).