Staphylococcus aureus is one of the most prominent of all bacterial pathogens. Its ability to cause disease is dependent on the production of a diverse array of virulence factors in a coordinated fashion. In many cases, this ultimately results in formation of a bacterial biofilm. This biofilm greatly compromises the efficacy of antimicrobial therapy. Current models of the regulatory circuits required to modulate these processes are based almost exclusively on experiments done with the laboratory strain RN6390. However, our preliminary results have demonstrated that there are important differences between RN6390 and clinical isolates. The central hypothesis behind this proposal is that defining global regulatory circuits in clinical isolates will facilitate our understanding of staphylococcal pathogenesis and biofilm formation and that this may lead to the identification of new therapeutic targets capable of limiting biofilm formation and thereby increasing the efficacy of conventional antimicrobial agents. Based on this, we propose to define regulatory circuits of S. aureus in the more relevant context of clinical isolates with a specific focus on biofilm formation and virulence in our animal models (Aim 1 ).These experiments will be done in a defined set of strains chosen based on the fact that they are representative of the most commonly encountered clinical isolates. We will also assess the impact of specific mutations that play a role in biofilm formation on the efficacy of antimicrobial therapy in vivo (Aim 2). Additionally, we have confirmed that mutation of one regulatory locus (sarA) in clinical isolates results in a reduced capacity to form a biofilm, reduced virulence in our animal models, and increases susceptibility to at least some anti-staphylococcal agents. Based on this, we have also included mechanistic studies of SarA function, the central issue being how SarA binds to cis DMA elements associated with its target genes (Aim 3). These studies will allow us to explore the possibility of using peptide-nucleic acids as specific inhibitors of SarA that can be used to limit the ability of clinical isolates to form a biofilm. Lay description: Staphylococcus aureus causes devastating infections, and our current understanding of how this happens is inaccurate because almost all studies have been done with a laboratory strain rather than the clinical isolates that most commonly cause disease. This proposal is aimed at correcting these inaccuracies and ultimately developing therapeutic agents that can inhibit the ability of S. aureus to cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074935-05
Application #
8080338
Study Section
Special Emphasis Panel (ZRG1-BACP-B (09))
Program Officer
Huntley, Clayton C
Project Start
2007-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$311,427
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Cue, David; Junecko, Jennifer M; Lei, Mei G et al. (2015) SaeRS-dependent inhibition of biofilm formation in Staphylococcus aureus Newman. PLoS One 10:e0123027
Atwood, Danielle N; Loughran, Allister J; Courtney, Ashleah P et al. (2015) Comparative impact of diverse regulatory loci on Staphylococcus aureus biofilm formation. Microbiologyopen 4:436-51
Loughran, Allister J; Atwood, Danielle N; Anthony, Allison C et al. (2014) Impact of individual extracellular proteases on Staphylococcus aureus biofilm formation in diverse clinical isolates and their isogenic sarA mutants. Microbiologyopen 3:897-909
Cassat, James E; Smeltzer, Mark S; Lee, Chia Y (2014) Investigation of biofilm formation in clinical isolates of Staphylococcus aureus. Methods Mol Biol 1085:195-211
May, Folasade P; Bromley, Erica G; Reid, Mark W et al. (2014) Low uptake of colorectal cancer screening among African Americans in an integrated Veterans Affairs health care network. Gastrointest Endosc 80:291-8
Hart, Mark E; Tsang, Laura H; Deck, Joanna et al. (2013) Hyaluronidase expression and biofilm involvement in Staphylococcus aureus UAMS-1 and its sarA, agr and sarA agr regulatory mutants. Microbiology 159:782-91
Cassat, James E; Hammer, Neal D; Campbell, J Preston et al. (2013) A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host Microbe 13:759-72
Zielinska, Agnieszka K; Beenken, Karen E; Mrak, Lara N et al. (2012) sarA-mediated repression of protease production plays a key role in the pathogenesis of Staphylococcus aureus USA300 isolates. Mol Microbiol 86:1183-96
Quave, Cassandra L; Estévez-Carmona, Miriam; Compadre, Cesar M et al. (2012) Ellagic acid derivatives from Rubus ulmifolius inhibit Staphylococcus aureus biofilm formation and improve response to antibiotics. PLoS One 7:e28737
Hobby, Gerren H; Quave, Cassandra L; Nelson, Katie et al. (2012) Quercus cerris extracts limit Staphylococcus aureus biofilm formation. J Ethnopharmacol 144:812-5

Showing the most recent 10 out of 19 publications