Non-Native Peptides Capable of Pan-Activating the <i>agr</i> Quorum Sensing System across Multiple Specificity Groups of <i>Staphylococcus epidermidis</i>

Abstract

<i>Staphylococcus epidermidis</i> is a leading cause of hospital-acquired infections. Traditional antibiotics have significantly reduced efficacy against this pathogen due to its ability to form biofilms on abiotic surfaces and drug resistance. The accessory gene regulator (<i>agr</i>) quorum sensing system is directly involved in <i>S. epidermidis</i> pathogenesis. Activation of <i>agr</i> is achieved via binding of the autoinducing peptide (AIP) signal to the extracellular sensor domain of its cognate receptor, AgrC. Divergent evolution has given rise to four <i>agr</i> specificity groups in <i>S. epidermidis</i> defined by the unique AIP sequence used by each group (AIPs-I-IV) with observed cross-group activities. As <i>agr</i> agonism has been shown to reduce biofilm growth in <i>S. epidermidis</i>, the development of pan-group activators of the <i>agr</i> system is of interest as a potential antivirulence strategy. To date, no synthetic compounds have been identified that are capable of appreciably activating the <i>agr</i> system of more than one specificity group of <i>S. epidermidis</i> or, to our knowledge, of any of the other Staphylococci. Here, we report the characterization of the structure-activity relationships for <i>agr</i> agonism by <i>S. epidermidis</i> AIP-II and AIP-III and the application of these new SAR data and those previously reported for AIP-I for the design and synthesis of the first multigroup <i>agr</i> agonists. These non-native peptides were capable of inducing the expression of critical biofilm dispersal agents (i.e., phenol-soluble modulins) in cell culture and represent new tools to study the role of quorum sensing in <i>S. epidermidis</i> infections.