Increasing AIP macrocycle size reveals key features of agr activation in Staphylococcus aureus Journal Article


Authors: Johnson, J. G.; Wang, B.; Debelouchina, G. T.; Novick, R. P.; Muir, T. W.
Article Title: Increasing AIP macrocycle size reveals key features of agr activation in Staphylococcus aureus
Abstract: The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two-promoter regulon with allelic variability that produces a quorum-sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum-sensing pathway has fueled tremendous interest in understanding the structure-activity relationships underlying the AIP-AgrC interaction. The defining structural feature of the AIP is a 16-membered, thiolactone-containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogues featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function by using both established cell-based reporter gene assays and newly developed in vitro AgrC-I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, three-points-of-contact interaction between the AIP macrocycle and AgrC. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords: unclassified drug; protein function; gene expression; gene locus; in vitro study; peptide; structure activity relation; autophosphorylation; bacterial virulence; bacteria (microorganisms); gene activation; biological activity; protein synthesis; reporter gene; staphylococcus aureus; structure-activity relationships; proton nuclear magnetic resonance; macrocyclic compound; quorum sensing; global change; regulator gene; population density; priority journal; article; autoinducing peptides; autoinducing peptide; protein histidine kinase; thiolactone; accessory gene regulator
Journal Title: ChemBioChem
Volume: 16
Issue: 7
ISSN: 1439-4227
Publisher: Wiley V C H Verlag Gmbh  
Date Published: 2015-05-04
Start Page: 1093
End Page: 1100
Language: English
DOI: 10.1002/cbic.201500006
PROVIDER: scopus
PUBMED: 25801678
PMCID: PMC4589298
DOI/URL:
Notes: Export Date: 3 June 2015 -- Source: Scopus
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