Hypericin enhances ?-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus.
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ABSTRACT: Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus (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 Staphylococcus aureus. 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 (e.g., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced sarA expression, and subsequently decreased mecA, and virulence-related regulators (e.g., agr RNA?) and genes (e.g., fnbA and hla) expression in the studied MRSA strain. Importantly, the in vitro synergistic effect of hypericin with ?-lactam antibiotic (e.g., oxacillin) translated into in vivo 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 sarA inhibition, and may allow us to repurpose the use of ?-lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (e.g., oxacillin).
SUBMITTER: Wang G
PROVIDER: S-EPMC6900551 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
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