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

• 来源期刊: 药学学报（英文版）
• 关键词: Hypericin β-Lactams MRSA Synergistic effect SarA
• 年，卷（期）: 2019,（6）
• 页码范围: 1174-1182
• 页数: 9页
• 语种: 英文

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-1actam 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-1actam 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-1actam 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 ofβ-lactam antibiotics,which are normally ineffective in the treatment of MRSA infections (e.g.,oxacillin).