Long-term goals are to understand the pathogenesis of methicillin-resistant Staphylococcus aureus (MRSA) that secrete superantigens (SAgs) such as enterotoxin (SE) B or C, SE-like Q, and toxic shock syndrome toxin-1 (TSST-1) and Bacillus anthracis. MRSA are emerging pathogens and their SAgs category B select agents. B. anthracis is a category A select agent. We have assembled two projects that are described below. Project 1. High-Affinity Molecules to Inhibit Superantigen Function. When produced in vivo or when purposely administered, SAgs are exceptionally toxic (TSS symptoms at doses of 0.1 ng/human). Most MRSA associated with post-influenza TSS, necrotizing pneumonia, and purpura fulminans produce SEB, SEC, SE-like Q, and TSST-1.
Specific Aim 1. To engineer and characterize V(3-T cell receptor (TCR) regions that bind with high affinity to SAgs and neutralize them, most importantly SEB, SEC, SE-like Q, and TSST-1.
Specific Aim 2. To engineer and characterize MHC II regions that bind with high affinity to SAgs and neutralize their activities.
Specific Aim 3. To test the ability of soluble Vp-TCRs and MHC Ms to neutralize the activities of SAgs in vitro and in vivo in rabbits. Project. 2: Inhibitors of SrrA-SrrB and BrrA-BrrB Regulated Exotoxin Production. MRSA require oxygen for exotoxin production. This observation led to identification of a """"""""Master Switch"""""""" two-component system required for oxygen control of exotoxin production in MRSA. This system, designated srrA-srrB, represses exotoxin production and virulence under conditions of low oxygen. Recently, a homolog in B. anthracis was described-BrrA-BrrB. BrrA-BrrB functions to induce anthrax toxin genes and facilitate disease production.
The aims will provide a foundation for interfering with diseases by developing small molecule inhibitors.
Specific Aim 4. To characterize SrrB and BrrB as histidine kinases with ability to phosphorylate SrrA and BrrA.
Specific Aim 5. To evaluate small molecule inhibitors of SrrB/BrrB to prevent production of SAgs, anthrax toxin, and B. anthracis capsule.
Aim 6. To determine the 3-D structures of SrrB and BrrB proteins or extracellular/intracellular domains and combined with menaquinone or inhibitors.
Highly antibiotic resistant Staphylococcus aureus are the most significant invasive pathogens in the United States. Bacillus anthracis and staphylococcal exotoxins (anthrax toxins and superantigens) are highly toxic to humans. We propose to engineer molecules to neutralize Staphylococcus aureus exotoxins and identify small molecule inhibitors that prevent production of staphylococcal and Bacillus anthracis exotoxins.
|Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7|
|Agostoni, Marco; Waters, Christopher M; Montgomery, Beronda L (2016) Regulation of biofilm formation and cellular buoyancy through modulating intracellular cyclic di-GMP levels in engineered cyanobacteria. Biotechnol Bioeng 113:311-9|
|Duckworth, Benjamin P; Wilson, Daniel J; Aldrich, Courtney C (2016) Measurement of Nonribosomal Peptide Synthetase Adenylation Domain Activity Using a Continuous Hydroxylamine Release Assay. Methods Mol Biol 1401:53-61|
|Kuhn, Misty L; Alexander, Evan; Minasov, George et al. (2016) Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis. ACS Infect Dis 2:579-591|
|Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73|
|Park, Sung Ryeol; Tripathi, Ashootosh; Wu, Jianfeng et al. (2016) Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat Commun 7:10710|
|Hoang, Ky Van; Chen, Carolyn G; Koopman, Jacob et al. (2016) Identification of Genes Required for Secretion of the Francisella Oxidative Burst-Inhibiting Acid Phosphatase AcpA. Front Microbiol 7:605|
|Lin, Ann E; Beasley, Federico C; Olson, Joshua et al. (2015) Role of Hypoxia Inducible Factor-1Î± (HIF-1Î±) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog 11:e1004818|
|Becker, Russell E N; Bubeck Wardenburg, Juliane (2015) Staphylococcus aureus and the skin: a longstanding and complex interaction. Skinmed 13:111-9; quiz 120|
|Lopera, Juan G; Falendysz, Elizabeth A; Rocke, Tonie E et al. (2015) Attenuation of monkeypox virus by deletion of genomic regions. Virology 475:129-38|
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