Staphylococcus aureus is a major community and hospital-acquired pathogen causing superficial skin and life-threatening infections worldwide. The continued emergence of multiple-antibiotic resistant strains of S. aureus, especially methicillin and vancomycin-intermediate resistant strains, is of significant public health concern. This organism has evolved into a series of two-component signal transduction systems (TCS) in order to sense its immediate surroundings and to modulate cellular responses and the expression of virulence genes. Our long-term goals are to elucidate the regulatory mechanisms controlling the expression of genes involved in critical pathways in order to identify novel targets for delivering efficacious preventive and/or therapeutic agents against S. aureus. The specific hypothesis is that a novel S. aureus TCS (yhcSR} controls the genes/operons required for bacterial growth. Our hypothesis has been formulated on the basis of our preliminary data that 1) the down-regulation of YhcS (histdine kinase) expression inhibits bacterial growth in a dose-dependent manner; 2) the over-expression of either YhcS or YhcR also impedes bacterial growth; and 3) yhcR encodes a response regulator (DNA-Binding protein) and has many different homologs in various Gram-positive pathogens. Therefore, the objectives of this proposal are to characterize the yhcSR system, identify genes/operons that are controlled by yhcSR, and determine the genes/operons that yhcSR directly regulates, which are required for bacterial survival. We will pursue the following specific aims to test our central hypothesis. First, we will characterize the yhcSR system to address why it is important for bacterial growth. Second, we will identify the target genes directly regulated by yhcSR and determine the importance of the identified gene products for bacterial growth. Third, we will determine what controls yhcSR expression. These results will not only provide new insights into the regulatory mechanisms of bacterial physiology, but may also lead to the identification of novel targets for developing preventive and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057451-02
Application #
7069489
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Korpela, Jukka K
Project Start
2005-06-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$255,478
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hall, Jeffrey W; Yang, Junshu; Guo, Haiyong et al. (2017) The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production. Infect Immun 85:
Zheng, Li; Yan, Meiying; Fan, Frank et al. (2015) The Essential WalK Histidine Kinase and WalR Regulator Differentially Mediate Autolysis of Staphylococcus aureus RN4220. J Nat Sci 1:
Lei, Ting; Yang, Junshu; Ji, Yinduo (2015) Determination of essentiality and regulatory function of staphylococcal YeaZ in branched-chain amino acid biosynthesis. Virulence 6:75-84
Lei, Ting; Becker, Aaron; Ji, Yinduo (2014) Transcriptomic analysis of Staphylococcus aureus using microarray and advanced next-generation RNA-seq technologies. Methods Mol Biol 1085:213-29
Yang, Junshu; Ji, Yinduo (2014) Investigation of Staphylococcus aureus adhesion and invasion of host cells. Methods Mol Biol 1085:187-94
Lei, Ting; Wang, Lei; Chen, Chi et al. (2014) Metabolomic investigation of methicillin-resistant Staphylococcus aureus. Methods Mol Biol 1085:251-8
Yang, Junshu; Liang, Xudong; Ji, Yinduo (2013) The mutated staphylococcal H35A ?-toxin inhibits adhesion and invasion of Staphylococcus aureus and group A streptococci. Virulence 4:77-81
Ji, Yinduo; Lei, Ting (2013) Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria. Sci Prog 96:43-60
Hall, Jeffrey W; Ji, Yinduo (2013) Sensing and Adapting to Anaerobic Conditions by Staphylococcus aureus. Adv Appl Microbiol 84:1-25
Yan, Meiying; Hall, Jeffrey W; Yang, Junshu et al. (2012) The essential yhcSR two-component signal transduction system directly regulates the lac and opuCABCD operons of Staphylococcus aureus. PLoS One 7:e50608

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