title: Simplified AIP-II Peptidomimetics Are Potent Inhibitors of Staphylococcus aureus AgrC Quorum Sensing Receptors.
abstract: The bacterial pathogen Staphylococcus aureus controls many aspects of virulence by using the accessory gene regulator (agr) quorum sensing (QS) system. The agr system is activated by a macrocyclic peptide signal known as an autoinducing peptide (AIP). We sought to develop structurally simplified mimetics of AIPs for use as chemical tools to study QS in S. aureus. Herein, we report new peptidomimetic AgrC receptor inhibitors based on a tail-truncated AIP-II peptide that have almost analogous inhibitory activities to the parent peptide. Structural comparison of one of these peptidomimetics to the parent peptide and a highly potent, all-peptide-derived, S. aureus agr inhibitor (AIP-III D4A) revealed a conserved hydrophobic motif and overall amphipathic nature. Our results suggest that the AIP scaffold is amenable to structural mimicry and minimization for the development of synthetic agr inhibitors.
authors.affiliation: Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI, 53706, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Vasquez
authors.affiliation: Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI, 53706, USA.|Present address: Department of Chemistry, University of Nevada, 1664 N. Virginia Street, Reno, NV, 89557, USA.
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.affiliation: National Magnetic Resonance Facility at Madison, University of Wisconsin, 433 Babcock Drive, Madison, WI, 53706, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cornilescu
authors.affiliation: Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI, 53706, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Tyler
authors.affiliation: Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI, 53706, USA.
authors.forename: Helen E
authors.identifier: 0000-0003-4261-8194
authors.initials: HE
authors.lastname: Blackwell
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D057786:Peptidomimetics; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics; D013211:Staphylococcus aureus / Q000201:enzymology / Q000502:physiology*
chemical_list: C414532:AgrD protein, Staphylococcus; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus
keywords: Staphylococcus aureus; accessory gene regulator; autoinducing peptides; peptidomimetics; quorum sensing