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

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).

In vitro Antimicrobial Activity and the Mechanism of Berberine Against Methicillin-Resistant Staphylococcus aureus Isolated from Bloodstream Infection Patients

“…For each interaction, the fractional inhibitory concentration (FIC) was calculated for each agent: synergism, antagonism, and indifference correlated with FIC ≤ 0.5, FIC > 4, and 0.5 < FIC ≤ 4, respectively. 21 …”

“… 23 Delivering approximately 5×10 5 CFU*mL −1 of MRSA cells to 96-well plates containing diluted BER and antibiotics in brain heart infusion broth (BHI, OXIOD) supplemented with 0.5% glucose. 21 Wells containing only the BHI were used as the negative control, whereas wells containing bacteria grown in BHI were used as the positive control. The suspension was transferred to 96-well plates with individual compounds and combinations (4 × MIC, 2 × MIC, 1 × MIC, 1/2 × MIC, 1/4 × MIC of BER, 1/16 × MIC, 1/32 × MIC of RIF, or 1/4 × MIC of CLI) treated and incubated for 18 h at 37°C.…”

Effects of Traditional Chinese Medicine and its Active Ingredients on Drug-Resistant Bacteria

“…These combinations completely inhibited the growth of bacteria after 24 h (Joung et al, 2015). Studies have found that hypericin and β-lactam antibiotics such as oxacillin have anti-MRSA ability (Wang et al, 2019). Cha et al (2014) demonstrated that cryptotanshinone combined with ampicillin, oxacillin, or vancomycin had synergistic effects on methicillin-resistant and vancomycinresistant S. aureus and greatly inhibited the growth of bacteria.…”

Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria

“…Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and β-lactam antibiotic resistance in S. aureus 122 - 124 . Interestingly, antidepressant and antiviral hypericin was found to significantly reduce sarA , mecA and virulence-related regulator expression, thereby enhancing the activity of β-lactam antibiotics against MRSA 125 .…”