摘要
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 andβ-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 onβ-lactam antibiotics susceptibility and mechanism(s)of its activity.We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations ofβ-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 mecAy and virulence-related regulators(e.g.,agr RNAIII)and genes(e.g.,fnbA and hla)expression in the studied MRSA strain.Importantly,the in vitro synergistic effect of hypericin withβ-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 ofβ-lactam resistance againstMRSA through sarA inhibition,and may allow us to repurpose the use ofβ-lactam antibiotics,which are normally ineffective in the treatment of MRSA infections(e.g.,oxacillin).
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 andβ-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 onβ-lactam antibiotics susceptibility and mechanism(s) of its activity.We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations ofβ-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 mecAy and virulence-related regulators (e.g.,agr RNAIII) and genes (e.g.,fnbA and hla) expression in the studied MRSA strain.Importantly,the in vitro synergistic effect of hypericin withβ-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 ofβ-lactam resistance againstMRSA through sarA inhibition,and may allow us to repurpose the use ofβ-lactam antibiotics,which are normally ineffective in the treatment of MRSA infections (e.g.,oxacillin).
基金
supported in part by CAMS Initiative for Innovative Medicine(grant numbers 2016-I2M-2-002 and 2016-I2M3-014,China)
National Mega-project for Innovative Drugs(grant number 2018ZX09721001,China)
the National Science Foundation of China(grant number 81621064,China).
