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 ac...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).展开更多
As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in v...As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical strains.Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.展开更多
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).
文摘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 by the National Natural Science Foundation of China (Grant Nos. 81621064 and 81361138020)CAMS Initiative for Innovative Medicine (Grant No. 2016-I2M-3-014, China)+1 种基金PUMC Youth Fund (Grant No. 3332013145, China)National Mega-project for Innovative Drugs (Grant No. 2018ZX09721001, China)
文摘As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical strains.Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.
