Simplified Autoinducing Peptide Mimetics with Single-Nanomolar Activity Against the Staphylococcus aureus AgrC Quorum Sensing Receptor
Abstract
Staphylococcus aureus is a leading cause of hospital-acquired infections worldwide, and cases of community-acquired infections are becoming more prevalent. The production of numerous virulence factors in S. aureus is under the control of the accessory gene regulator (agr) quorum sensing (QS) system. S. aureus upregulates agr at high cell density by secreting a peptide pheromone, or autoinducing peptide (AIP), which is detected by its cognate transmembrane receptor, AgrC. The extracellular AIP binding site of AgrC represents an attractive target for inhibition of the agr system and, thereby, QS-controlled virulence in S. aureus. Nonnative peptides and, more recently, peptidomimetics have been reported to inhibit the AgrC receptor and represent useful chemical tools to study the role of QS in S. aureus infections. We seek to expand beyond peptide-like scaffolds to generate AgrC modulators with enhanced stability, solubility, and synthetic accessibility relative to these compounds, while maintaining their high potencies. Toward this goal, we report herein a study of the structure-activity relationships responsible for the activity of a recently reported simplified AIP mimetic and AgrC antagonist, n7OFF, and the discovery of a new ...Continue Reading
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