Probiotic disruption of quorum sensing reduces virulence and increases cefoxitin sensitivity in methicillin-resistant Staphylococcus aureus

Abstract

Therapies which target quorum sensing (QS) systems that regulate virulence in methicillin-resistant Staphylococcus aureus (MRSA) are a promising alternative to antibiotics. QS systems play a crucial in the regulation of MRSA antibiotic resistance, exotoxin production, antioxidant protection and immune cell evasion, and are therefore attractive therapeutic targets to reduce the virulence of a pathogen. In the present work the the effects of bioactive peptides isolated from two strains of lactic acid bacteria were tested against antibiotic resistance, carotenoid production, resistance to oxidative killing and biofilm structure in two clinical MRSA isolates. The results obtained from fractional-inhibitory concentration assays with bulk and semi-purified bioactive molecules showed a significant synergistic effect increasing cefoxitin mediated killing of MRSA. This was coupled to a six-fold decrease of the major membrane pigment staphyloxanthin, and a 99% increase in susceptibility to oxidative stress mediated killing. Real-time quantitative PCR analysis of the QS-genes agrA and luxS, showed differential expression between MRSA strains, and a significant downregulation of the hemolysin gene hla. Light microscopy and scanning electron microscopy revealed alteration in biofilm formation and clustering behavior. These results demonstrate that bioactive metabolites may be effectively applied in tandem with beta-lactam antibiotics to sensitize MRSA to cefoxitin. Moreover, these results shown that several key QS-controlled virulence mechanisms are diminished by probiotic metabolites.

Synthesis, Characterization, and Docking Study of Novel Thioureidophosphonate-Incorporated Silver Nanocomposites as Potent Antibacterial Agents

“…However, the reported data about their antibiofilm mechanism of action towards MRSA biofilm are directed for hybrid α-APs; thus, the inhibitory actions of mentioned α-APs analogues were proposed [ 65 , 73 ]. First, the interference with the quorum sensing (QS) system, which represents a major source of biofilm nutrition and protection, could be a reason [ 74 ]. Moreover, the interaction with the extracellular DNA (e-DNA) of biofilm affects its integrity and biological functionality.…”

Collaterally Sensitive β-Lactam Drugs as an Effective Therapy against the Pre-Existing Methicillin Resistant Staphylococcus aureus (MRSA) Biofilms

“…Studies of MRSA resistance factors at the molecular level would greatly enhance our understanding of the drug interactions with its resistance factors and pave the way for designing effective treatments. Alternative approaches like phage therapy [ 31 ], nanoparticles [ 32 ], radiation therapy [ 33 ], and quorum sensing inhibition [ 34 ] have also been making grounds against MRSA resistance. Collateral synergy, repurposing of existing drugs, and the development of novel molecules that target different resistance factors in S. aureus are all essential to effectively combating this notorious pathogen [ 35 ].…”

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

“…Synergy has been investigated and reported largely for multiple antibiotics( 57 ). In the face of the emergence of multi-drug resistant organisms, antibiotic synergy with non-antibiotics has also gained interest( 31 , 58 ) Most of the work has focused on the synergy between antibiotics and non-conventional antimicrobial strategies such as the use of bacteriophages, antimicrobial peptides, and small molecules, inhibiting vital bacterial processes( 59 – 62 ). Recently, there has also been considerable interest in repurposing non-antibiotic drugs for the purpose of infection prevention and management( 63 , 64 ).…”