Pseudomonas aeruginosa metabolism in the cystic fibrosis lung
Cystic fibrosis of the lung is an autosomal recessive disease caused by defects in the Cystic Fibrosis Transmembrane conductance Regulator. While current treatments and interventions have greatly reduced morbidity and increased life expectancy in this population, cystic fibrosis patients face chronic infection of the lung. These chronic infections cause a chronic inflammatory state of the lung to develop, leading to slow degradation of the lung parenchyma and expansion of the conductive pathways, a disease known as bronchiectasis. Treatment at the late stages of this pulmonary disease is by heart and lung transplantation, a surgical intervention that carries significant risk as well as limited by the total availability of such organs. A potential intervention in this disease process that may significantly reduce the progression of bronchiectasis is in the effective removal of pathogenic organisms from the cystic fibrosis lung. Of the various organisms that cause chronic infection of the cystic fibrosis lung, Pseudomonas aeruginosa demonstrates the highest prevalence of infection and greatest correlated risk of morbidity and mortality in this population. Pseudomonas aeruginosa is a Gram negative bacterial species know for a wide range of opportunistic infections (e.g. burn wounds, urinary tract infections secondary to catheterization, and ventilator-associated pneumonia) and a diverse range of environments that it inhabits. Effective treatment of P. aeruginosa infection is greatly complicated due to its intrinsic resistance to many different classes of antibiotics as well as the rapid development of resistance to treatment during chronic cystic fibrosis lung infection. A greater understanding of the metabolic phenotypes of P. aeruginosa may lead to the development of both better clinical tests monitoring the state of infection of the lung as well as the intelligent design of pharmaceutical interventions that target metabolic pathways important to growth in this organism during infection. In this dissertation, I present the quantified carbon metabolism of six cystic fibrosis P. aeruginosa isolates and the laboratory reference strain PA01. In these studies, I demonstrate the difference of metabolism under glucose only minimal media growth (M9) and in a media formulated to mimic the cystic fibrosis lung under aerobic and anoxic growth (Simplified Synthetic Cystic Fibrosis sputum Media). These studies reveal shared and divergent metabolic phenotypes across several isolates from different geographical as well as genetic backgrounds. These studies also identify the importance of the glyoxylate cycle and polyamine metabolism during the growth of P. aeruginosa and to demonstrate the variation in utilization of other metabolic sub-systems of central carbon metabolism. Finally, these studies demonstrate the suboptimal biomass production of P. aeruginosa and identify overproduction of reductant as a key product of the central metabolism of P. aeruginosa. Overall, this research makes substantial progress in understanding not only the metabolism of P. aeruginosa in the cystic fibrosis lung but identifying key metabolic pathways for future investigation that may have a significant impact in the understanding of biofilm formation and pathogenic infection of other bacteria.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Opperman, Michael Jay
- Thesis Advisors
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Shachar-Hill, air
- Committee Members
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Arvidson, Cindy
Vieille, Claire
Worden, Robert
He, Sheng Yang
- Date
- 2016
- Subjects
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Cystic fibrosis
Lungs--Diseases--Research
Pseudomonas aeruginosa infections
Pseudomonas aeruginosa
Metabolism
- Program of Study
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Cell and Molecular Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xii, 187 pages
- ISBN
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9781339702339
1339702339
- Permalink
- https://doi.org/doi:10.25335/s1zs-6s16