| Title: | Simplified Autoinducing Peptide Mimetics with Single-Nanomolar Activity Against the Staphylococcus aureus AgrC Quorum Sensing Receptor |
| Author(s): | Vasquez JK; Blackwell HE; |
| Address: | "Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States" |
| DOI: | 10.1021/acsinfecdis.9b00002 |
| ISSN/ISBN: | 2373-8227 (Electronic) 2373-8227 (Linking) |
| Abstract: | "Staphylococcus aureus is a leading cause of hospital-acquired infections worldwide, and cases of community-acquired infections are becoming more prevalent. The production of numerous virulence factors in S. aureus is under the control of the accessory gene regulator (agr) quorum sensing (QS) system. S. aureus upregulates agr at high cell density by secreting a peptide pheromone, or autoinducing peptide (AIP), which is detected by its cognate transmembrane receptor, AgrC. The extracellular AIP binding site of AgrC represents an attractive target for inhibition of the agr system and, thereby, QS-controlled virulence in S. aureus. Nonnative peptides and, more recently, peptidomimetics have been reported to inhibit the AgrC receptor and represent useful chemical tools to study the role of QS in S. aureus infections. We seek to expand beyond peptide-like scaffolds to generate AgrC modulators with enhanced stability, solubility, and synthetic accessibility relative to these compounds, while maintaining their high potencies. Toward this goal, we report herein a study of the structure-activity relationships responsible for the activity of a recently reported simplified AIP mimetic and AgrC antagonist, n7OFF, and the discovery of a new AIP mimetic, Bnc3, which has low- to sub-nanomolar inhibitory activity in all four S. aureus agr specificity groups. NMR structural studies of Bnc3 revealed hydrophobic and hydrophilic faces that are likely critical for AgrC antagonism, in agreement with prior studies of peptide-derived inhibitors. Bnc3 represents an important transition compound toward the development of small-molecule AgrC antagonists" |
| Keywords: | "Bacterial Proteins/*antagonists & inhibitors/*chemistry/genetics/metabolism Humans Peptides/*chemistry/pharmacology Peptides, Cyclic/*chemistry/genetics/metabolism Protein Kinases/genetics/metabolism Quorum Sensing/drug effects Staphylococcal Infections/m;" |
| Notes: | "MedlineVasquez, Joseph K Blackwell, Helen E eng T32 GM008505/GM/NIGMS NIH HHS/ S10 OD020022/OD/NIH HHS/ P41 GM066326/GM/NIGMS NIH HHS/ S10 OD012245/OD/NIH HHS/ S10 RR002781/RR/NCRR NIH HHS/ P41 GM103399/GM/NIGMS NIH HHS/ S10 RR008438/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2019/03/01 ACS Infect Dis. 2019 Apr 12; 5(4):484-492. doi: 10.1021/acsinfecdis.9b00002. Epub 2019 Mar 13" |
