EXCEED THE SPACE PROVIDED. Pseudomonas aeruginosa is a malicious opportunistic pathogen both in terms of the severity and the outcome of infections it causes. A significant proportion of patients with cystic fibrosis (CF) is colonized at an early age (1-2yrs), and most ultimately succumbs to a chronic lung infection from P. aeruginosa. The myriad of virulence determinants, including colonization factors and toxins that P. aeruginosa produces contribute to its pathogenic potential. Unfortunately, the exact contribution of these factors, alone or in combination, to even the simplest kind of P. aeruginosa infection has not yet been elucidated. Expression of all the identified major virulence determinants in this organism is regulated by a variety of environmental conditions, which the organism encounters at some point in its journey through the host. Consequently variations in available environmental iron undoubtedly contribute to the pathogenesis of P. aeruginosa infections. Production of specific virulence factors of this organism are induced in response to limiting amounts of iron, a natural occurring environment in mammalian hosts. The dynamic control of intracellular iron concentrations is paramount to all biological systems. One aspect of this issue is that, especially in an aerobic environment, biologically useful iron (i.e. Fe2*) is extremely limiting or it is highly insoluble (i.e.Fe3*). Accordingly, biological entities have evolved efficient mechanisms to acquire this nutrient from the insoluble form, which is generally in plentiful quantities. On the other hand, further acquisition of iron above biologically useful concentrations can have dire consequences for a cell. Excess free iron will catalyze the generation of highly reactive oxygen and nitrogen intermediates that will damage all known biological macromolecules. This conflict, in a major way is dealt with in a diverse array of pathogenic and commensal prokaryotic microbes, by repressor proteins, which play the key role in controlling iron homeostasis at the level of transcription. The ferric uptake regulator (Fur) serves this function in many bacteria. In fact, in the opportunistic pathogen P. aeruginosa Fur (PA-Fur) is an essential protein that controls the expression of genes involved in the acquisition of environmental iron, including those that contribute to its virulence. This project will investigate the role of PA-Fur and PA-Fur regulated genes in the pathogenesis of P. aeruginosa infections for the ultimate goal or developing novel antimicrobial agents against this formidable opportunist. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI015940-26
Application #
6824065
Study Section
Special Emphasis Panel (ZRG1-BM-1 (06))
Program Officer
Taylor, Christopher E,
Project Start
1979-04-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
26
Fiscal Year
2005
Total Cost
$488,315
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Oglesby-Sherrouse, Amanda G; Djapgne, Louise; Nguyen, Angela T et al. (2014) The complex interplay of iron, biofilm formation, and mucoidy affecting antimicrobial resistance of Pseudomonas aeruginosa. Pathog Dis 70:307-20
Wiens, Jacinta R; Vasil, Adriana I; Schurr, Michael J et al. (2014) Iron-regulated expression of alginate production, mucoid phenotype, and biofilm formation by Pseudomonas aeruginosa. MBio 5:e01010-13
Ibarguren, Maitane; Sot, Jesús; Montes, L Ruth et al. (2013) Recruitment of a phospholipase C/sphingomyelinase into non-lamellar lipid droplets during hydrolysis of lipid bilayers. Chem Phys Lipids 166:12-7
Truan, Daphné; Vasil, Adriana; Stonehouse, Martin et al. (2013) High-level over-expression, purification, and crystallization of a novel phospholipase C/sphingomyelinase from Pseudomonas aeruginosa. Protein Expr Purif 90:40-6
Vasil, Michael L; Tomaras, Andrew P; Pritchard, Arthur E (2012) Identification and evaluation of twin-arginine translocase inhibitors. Antimicrob Agents Chemother 56:6223-34
Young, Robert L; Malcolm, Kenneth C; Kret, Jennifer E et al. (2011) Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One 6:e23637
Funken, Horst; Knapp, Andreas; Vasil, Michael L et al. (2011) The lipase LipA (PA2862) but not LipC (PA4813) from Pseudomonas aeruginosa influences regulation of pyoverdine production and expression of the sigma factor PvdS. J Bacteriol 193:5858-60
Oglesby-Sherrouse, Amanda G; Vasil, Michael L (2010) Characterization of a heme-regulated non-coding RNA encoded by the prrF locus of Pseudomonas aeruginosa. PLoS One 5:e9930
Jiang, Ziqing; Vasil, Adriana I; Hale, John D et al. (2008) Effects of net charge and the number of positively charged residues on the biological activity of amphipathic alpha-helical cationic antimicrobial peptides. Biopolymers 90:369-83
Lucarelli, Debora; Vasil, Michael L; Meyer-Klaucke, Wolfram et al. (2008) The Metal-Dependent Regulators FurA and FurB from Mycobacterium Tuberculosis. Int J Mol Sci 9:1548-1560

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