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 

作者机构：Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterTorranceCA 90502USA Beijing Key Laboratory of Antimicrobial AgentsInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Geffen School of Medicine at UCLALos AngelesCA 90095USA State Key Laboratory of Bioactive Substances and Function of Natural MedicineInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第6期

页      面：1174-1182页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 100401[医学-流行病与卫生统计学] 10[医学] 

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) 

主　　题：Hyperiein β-Lactams MRSA Synergistic effect SarA 

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 *** accessory regulator A(SarA),a global virulence regulator,plays a critical role in pathogenesis andβ-lactam antibiotic resistance in Staphylococcus *** is believed to act as an antibiotic,antidepressant,antiviral and non-specific kinase *** the current study,we investigated the impact of hypericin onβ-lactam antibiotics susceptibility and mechanism(s)of its *** 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 *** 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 ***,the in vitro synergistic effect of hypericin withβ-lactam antibiotic(e.g.,oxacillin)translated into in vivo therapeutic outcome in a murine MRSA bacteremia *** 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).