Highly Stable, Amide-Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus.
Blocking quorum sensing (QS) pathways has attracted considerable interest as an approach to suppress virulence in bacterial pathogens. Toward this goal, we recently developed analogues of a native autoinducing peptide (AIP-III) signal that can inhibit AgrC-type QS receptors and attenuate virulence phenotypes in Staphylococcus aureus. Application of these compounds is limited, however, as they contain hydrolytically unstable thioester linkages and have only low aqueous solubilities. Herein, we report amide-linked AIP analogues with greatly enhanced hydrolytic stabilities and solubilities relative to our prior analogues, whilst maintaining strong potencies as AgrC receptor inhibitors in S. aureus. These compounds represent powerful tools for the study of QS.
Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, WI, 53706, USA.|Current address: Department of Chemistry, University of Nevada, Reno, 1664 N. Virginia St., Reno, NV, 89557, USA.
Yftah
0000-0003-2052-6782
Y
Tal-Gan
Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, WI, 53706, USA.|Current address: Department of Chemistry, University of Vermont, 82 University Pl., Burlington, VT, 05405, USA.
Monika
M
Ivancic
National Magnetic Resonance Facility, University of Wisconsin-Madison, 433 Babcock Dr., Madison, WI, 53706, USA.
Gabriel
G
Cornilescu
Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, WI, 53706, USA.
Tian
T
Yang
Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, WI, 53706, USA. blackwell@chem.wisc.edu.
Helen E
0000-0003-4261-8194
HE
Blackwell
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
D000577:Amides; D001426:Bacterial Proteins; D010455:Peptides; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus
Staphylococcus aureus; autoinducing peptides; cyclic peptides; quorum sensing; virulence