Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillinresistant Staphylococcus aureus  

作　　者：Genzhu Wang Liang Li Xiukun Wang Xue Li Youwen Zhang Jie Yu Jiandong Jiang Xuefu You Yan Q.Xiong 

机构地区：[1]Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,Torrance,CA 90502,USA [2]Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [3]Geffen School of Medicine at UCLA,Los Angeles,CA 90095,USA [4]State Key Laboratory of Bioactive Substances and Function of Natural Medicine,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2019年第6期1174-1182,共9页药学学报（英文版）

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).

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).

关 键 词：Hyperiein Β-LACTAMS MRSA SYNERGISTIC effect SARA 

分 类 号：R515.3[医药卫生—内科学]