Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus - PubMed (original) (raw)

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

Genzhu Wang et al. Acta Pharm Sin B. 2019 Nov.

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).

Keywords: Hypericin; MRSA; SarA; Synergistic effect; β-Lactams.

© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

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Figures

Image 1

Graphical abstract

Fig. 1

Figure 1

In vitro time–killing curves of HYP, OXA, CFZ or NAF alone; and the combination of HYP with OXA, CFZ or NAF against MRSA JE2 strain. The data are the mean ± SD of MRSA counts in each group of at least two biological replicates.

Fig. 2

Figure 2

The effect of HYP (penal A), β_-lactam alone (penal B), and the combination of HYP with OXA (penal C), CFZ (penal D), or NAF (penal E) on biofilm formation in MRSA. Control or β_-lactam alone groups were set up as 1. Relative biofilm formation levels were represented as mean ± SD of at least two biological replicates. ∗_P < 0.05, ∗∗_P < 0.01, ∗∗∗P < 0.001; Penals A and B vs. control; Penal C, D and E vs. _β_-lactam alone.

Fig. 3

Figure 3

The effect of HYP or OXA alone and in combination on fibronectin binding in MRSA strain JE2. Control group was set up as 1. Relative fibronectin binding levels were represented as mean ± SD of at least two biological replicates. ∗P < 0.01, ∗∗P < 0.001 vs. control; ##P < 0.001 vs. OXA alone.

Fig. 4

Figure 4

The effect of HYP or OXA alone; and in combinations on sarA (Penal A), mecA (Penal B), fnbA (Penal C), agrRNAⅢ (Penal D) and hla (Penal E) expressions in MRSA. Control group was set up as 1. Relative transcript levels of sarA, mecA, fnbA, agrRNAⅢ, and hla were represented as mean ± SD of at least two biological replicates. ∗P < 0.05, ∗∗P < 0.01 vs. control; #P < 0.05, ##P < 0.01 vs. OXA alone.

Fig. 5

Figure 5

The effect of HYP on SarA binding ability to the mecA promoter.

Fig. 6

Figure 6

Therapeutic efficacy of HYP and OXA alone, and in combination in a mouse bacteremia model due to MRSA strain JE2. Each dot represents MRSA density in target tissues in the bacteremia model in one mouse (n = 6). Horizontal black bars indicate mean ± SD MRSA density in the target tissues. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.

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