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ACS Chem Biol. 2016 Jul 15;11(7):1982-91. doi: 10.1021/acschembio.6b00120. Epub 2016 May 18.

Structure-Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation.

Author information

1
Department of Chemistry, University of Wisconsin-Madison , 1101 University Ave., Madison, Wisconsin 53706, United States.
2
Department of Chemistry, University of Nevada, Reno , 1664 N. Virginia St., Reno, Nevada 89557, United States.
3
Department of Microbiology, University of Iowa Carver College of Medicine , 431 Newton Rd., Iowa City, Iowa 52242, United States.

Abstract

Staphylococcus epidermidis is frequently implicated in human infections associated with indwelling medical devices due to its ubiquity in the skin flora and formation of robust biofilms. The accessory gene regulator (agr) quorum sensing (QS) system plays a prominent role in the establishment of biofilms and infection by this bacterium. Agr activation is mediated by the binding of a peptide signal (or autoinducing peptide, AIP) to its cognate AgrC receptor. Many questions remain about the role of QS in S. epidermidis infections, as well as in mixed-microbial populations on a host, and chemical modulators of its agr system could provide novel insights into this signaling network. The AIP ligand provides an initial scaffold for the development of such probes; however, the structure-activity relationships (SARs) for activation of S. epidermidis AgrC receptors by AIPs are largely unknown. Herein, we report the first SAR analyses of an S. epidermidis AIP by performing systematic alanine and d-amino acid scans of the S. epidermidis AIP-I. On the basis of these results, we designed and identified potent, pan-group inhibitors of the AgrC receptors in the three S. epidermidis agr groups, as well as a set of AIP-I analogs capable of selective AgrC inhibition in either specific S. epidermidis agr groups or in another common staphylococcal species, S. aureus. In addition, we uncovered a non-native peptide agonist of AgrC-I that can strongly inhibit S. epidermidis biofilm growth. Together, these synthetic analogs represent new and readily accessible probes for investigating the roles of QS in S. epidermidis colonization and infections.

PMID:
27159024
PMCID:
PMC4946969
DOI:
10.1021/acschembio.6b00120
[Indexed for MEDLINE]
Free PMC Article

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