Staphylococcus aureus is a leading cause of diseases ranging from skin infections and food poisoning to life-threatening nosocomial infections. Increasing resistance of S. aureus isolates to glycopeptide antibiotics, most prominently vancomycin, is a major concern in today's intensive care units (ICUs). Many of the genes controlling the virulence of S. aureus, such as exotoxins, are regulated through a quorum sensing mechanism and may contribute to an antibiotic-resistant phenotype. The quorum sensing signaling molecules used by S. aureus are small cyclic peptides, also called autoinducing peptides (AIPs), whose primary structures, i.e. their amino acid sequences, vary among different strains of S. aureus. They are actively secreted through a transporter protein, AgrB, and bind in auto- and paracrine fashion to their cognate receptor, AgrC. This receptor is part of a classical two-component signal system that includes AgrA as the response regulator. The signal is transduced from AgrC to AgrA, triggering the expression of a particular set of virulence genes. It has been shown that by blocking this signaling pathway, the expression of virulence factors can be inhibited and S. aureus pathogenicity can be attenuated. Our proposed work includes the following aims: (1) synthesis of quorum sensing peptides and analogs from all 4 AlP subgroups of S. aureus; (2) selection of fully human antibody fragments against these peptides through the use of phage display technology; (3) selection and identification of human antibodies and peptides that bind to the extracellular domains of AgrB or AgrC from AlP-subgroup I S. aureus; (4) evaluation and characterization of the selected peptides and antibodies for their ability to successfully block the agr-based signaling cascade of AlP-subgroup I S. aureus. The work proposed herein represents a novel strategy to combat antibiotic resistance in S. aureus.
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