The agr locus encodes the central regulatory system for staphylococcal pathogenesis and other stress-related functions. It is a quorum-sensing system that contains a two-component signal transduction module, encoded by agrA and C, and a peptide autoinducer, encoded by agrD, that is the activating ligand. Natural variants exist that cross inhibit agr autoinduction in heterologous combinations, thus blocking pathogenesis. This is the continuation of a long-term program whose overall goal is to understand the mechanism of agr autoinduction, the role of the agr autoinduction circuit in the pathogenesis of staphylococcal disease, and the biological significance of agr variants and their biotypes.
Specific Aims for this period are: 1. To determine the mechanism of autoinducing peptide biosynthesis and the mechanism by which the mature secreted peptide interacts with its receptor, including both activation by cognate peptides and inhibition by heterologous ones. 2. To determine the role of the agr system in the pathogenesis of staphylococcal disease by following the expression of specific genes in vivo, the consequences of certain mutations, and the effects of the inducing or inhibiting peptides on the course of an experimental infection. 3. To characterize the agr specificity groups for traits or genes that are shared within a group and divergent between groups, with respect to pathogenic adaptations of the organism. Design and Methods: A direct ligand-binding assay using radioactive peptide will be developed to analyze receptor-ligand interactions. Variant peptides will be synthesized to delineate the structural and sequence requirements for receptor activation and inhibition. Other variants will be synthesized to enhance stability and activity in vivo to maximize the therapeutic efficacy of inhibiting virulence. Certain bacterial genes will be fused to a luciferase reporter, which will permit the monitoring of their expression as well as of the fate and persistence of infecting organisms in a murine infection model, by means of a luciferase-detecting imaging camera. This camera will monitor the effects of in vivo agr inhibition on the infecting organisms and on gene expression in vivo. Agr group-specific biotypes will be delineated to identify group-specific traits that may be correlated with pathogenic behavior - site and type of lesion, level of virulence, antibiotic resistance, etc.. ? ?
|Kim, Minyoung Kevin; Zhao, Aishan; Wang, Ashley et al. (2017) Surface-attached molecules control Staphylococcus aureus quorum sensing and biofilm development. Nat Microbiol 2:17080|
|Oslund, Rob C; Su, Xiaoyang; Haugbro, Michael et al. (2017) Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. Nat Chem Biol 13:1081-1087|
|Wang, Boyuan; Zhao, Aishan; Xie, Qian et al. (2017) Functional Plasticity of the AgrC Receptor Histidine Kinase Required for Staphylococcal Virulence. Cell Chem Biol 24:76-86|
|Wang, Boyuan; Muir, Tom W (2016) Regulation of Virulence in Staphylococcus aureus: Molecular Mechanisms and Remaining Puzzles. Cell Chem Biol 23:214-224|
|Wang, Boyuan; Zhao, Aishan; Novick, Richard P et al. (2015) Key driving forces in the biosynthesis of autoinducing peptides required for staphylococcal virulence. Proc Natl Acad Sci U S A 112:10679-84|
|Johnson, Jeffrey G; Wang, Boyuan; Debelouchina, Galia T et al. (2015) Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus. Chembiochem 16:1093-100|
|Wang, Boyuan; Zhao, Aishan; Novick, Richard P et al. (2014) Activation and inhibition of the receptor histidine kinase AgrC occurs through opposite helical transduction motions. Mol Cell 53:929-40|
|Ubeda, Carles; Tormo-Mas, Maria Angeles; Penades, Jose R et al. (2012) Structure-function analysis of the SaPIbov1 replication origin in Staphylococcus aureus. Plasmid 67:183-90|
|George Cisar, Elizabeth A; Geisinger, Edward; Muir, Tom W et al. (2009) Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinase AgrC. Mol Microbiol 74:44-57|
|Geisinger, Edward; Muir, Tom W; Novick, Richard P (2009) agr receptor mutants reveal distinct modes of inhibition by staphylococcal autoinducing peptides. Proc Natl Acad Sci U S A 106:1216-21|
Showing the most recent 10 out of 19 publications