Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus |
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Authors: | Jeffrey G Johnson Boyuan Wang Dr Galia T Debelouchina Prof Richard P Novick Prof Tom W Muir |
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Affiliation: | 1. Department of Chemistry, Princeton University, Frick Chemistry Building, Washington Road, Princeton, NJ 08544 (USA);2. Graduate Program, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (USA);3. Tri‐Institutional Training Program in Chemical Biology, Weil–Cornell/Memorial Sloan Kettering/Rockefeller University, New York, NY 10065 (USA);4. Skirball Institute, Department of Microbiology, NYU Medical Center, 540 First Avenue, New York, NY 10016 (USA) |
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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. |
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Keywords: | autoinducing peptides bacterial virulence biological activity quorum sensing structure– activity relationships |
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