Original articles
Genzhu Wang, Liang Li, Xiukun Wang, Xue Li, Youwen Zhang, Jie Yu, Jiandong Jiang, Xuefu You, Yan Q. Xiong. Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1174-1182

Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus
Genzhu Wanga,b, Liang Lia, Xiukun Wangb, Xue Lib, Youwen Zhangb, Jie Yub, Jiandong Jiangb,d, Xuefu Youb, Yan Q. Xionga,c
a Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
b Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
c Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
d 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
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 β-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 β-lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of β-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 RNAⅢ) and genes (e.g., fnbA and hla) expression in the studied MRSA strain. Importantly, the in vitro synergistic effect of hypericin with β-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 β-lactam resistance against MRSA through sarA inhibition, and may allow us to repurpose the use of β-lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (e.g., oxacillin).
Key words:    Hypericin    β-lactam    MRSA    Synergistic effect    SarA   
Received: 2019-02-22     Revised: 2019-05-11
DOI: 10.1016/j.apsb.2019.05.002
Funds: This study was supported in part by CAMS Initiative for Innovative Medicine (grant numbers 2016-I2M-2-002 and 2016-I2M-3-014, China), National Mega-project for Innovative Drugs (grant number 2018ZX09721001, China), the National Science Foundation of China (grant number 81621064, China). We are very grateful to Dr. Ambrose Cheung at Dartmouth Medical School (Hanover, New Hampshire, USA) for providing the purified SarA protein.
Corresponding author: Xuefu You, Yan Q. Xiong     Email:xuefuyou@hotmail.com;yxiong@ucla.edu
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Genzhu Wang
Liang Li
Xiukun Wang
Xue Li
Youwen Zhang
Jie Yu
Jiandong Jiang
Xuefu You
Yan Q. Xiong

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