Abstract
The therapeutic roles of phenolic blueberry (Vaccinium corymbosum) and blackberry (Rubus fruticosus) pomace (commercial byproduct) extracts (BPE) and their mechanism of actions were evaluated against methicillin resistant Staphylococcus aureus (MRSA). Five major phenolic acids of BPE, e.g., protocatechuic, p. coumaric, vanillic, caffeic, and gallic acids, as well as crude BPE completely inhibited the growth of vegetative MRSA in vitro while BPE+methicillin significantly reduced MRSA biofilm formation on plastic surface. In addition, BPE restored the effectiveness of methicillin against MRSA by down-regulating the expression of methicillin resistance (mecA) and efflux pump (norA, norB, norC, mdeA, sdrM, and sepA) genes. Antibiogram with broth microdilution method showed that MIC of methicillin reduced from 512 μg/mL to 4 μg/mL when combined with only 200 μg Gallic Acid Equivalent (GAE)/mL of BPE. Significant reduction in MRSA adherence to and invasion into human skin keratinocyte Hek001 cells were also noticed in the presence of BPE. BPE induced anti-apoptosis and anti-autophagy pathways through overexpression of Bcl-2 gene and down-regulation of TRADD and Bax genes (inducers of apoptosis pathway) in Hek001 cells. In summary, novel and sustainable prophylactic therapy can be developed with BPE in combination with currently available antibiotics, especially methicillin, against skin and soft tissue infections with MRSA.
Highlights
Staphylococcus aureus has historically been a tenacious human pathogen; in recent decades it has become an even more serious threat due to its acquisition of multiple antibiotic resistances (AR) (Wilkinson et al, 2005; Novick, 2008)
We found that the Minimum Bactericidal Concentration (MBC) of the tested phenolic acids including Protocatechuic acid, P. coumaric acid, Gallic acid, Vanillic acid, and Caffeic acid inhibited the growth of methicillin resistant Staphylococcus aureus (MRSA) in Cation Adjusted Muller Hinton Broth (CAMHB) liquid culture at concentrations ranging from 0.512 to 2.046 mg Gallic Acid Equivalent (GAE)/mL with P. coumaric acid being the most effective>1.028 mg GAE/mL of combination of these five phenolic acids were required for inhibiting the growth of MRSA
MBC of methicillin against MRSA was >512 μg Methicillin (μg/mL), whereas conjunction with various concentrations of blackberry pomace extracts (BPE) minimized the MBC of methicillin to as low as 4 μg/mL which is below the concentration range suggested by the CLSI for MRSA
Summary
Staphylococcus aureus has historically been a tenacious human pathogen; in recent decades it has become an even more serious threat due to its acquisition of multiple antibiotic resistances (AR) (Wilkinson et al, 2005; Novick, 2008). AR is growing worldwide, and the discovery of new antibiotics is not keeping pace with evolving bacterial resistance; alternative therapeutics is urgently required. Certain pathogenic S. aureus strains known as “superbugs” are exceptionally rigid and quickly develop protective mechanisms against synthetic antibiotics. One common superbug increasingly seen in hospitals and community is methicillin-resistant Staphylococcus aureus (MRSA). MRSA is resistant to most antibiotics currently available (Fair and Tor, 2014).
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