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Authors: Scheffler, Robert John
Advisors: Gitai, Zemer
Contributors: Molecular Biology Department
Subjects: Molecular biology
Issue Date: 2021
Publisher: Princeton, NJ : Princeton University
Abstract: Pseudomonas aeruginosa is a significant threat in both healthcare and industrial biofouling. Surface attachment of P. aeruginosa is particularly problematic as surface association induces virulence and biofilm formation, which hamper later antibiotic treatments. Here I developed a quantitative surface-dispersal assay and use it to show that P. aeruginosa itself produces factors that can stimulate its dispersal. Through bioactivity-guided fractionation, Mass Spectrometry, and Nuclear Magnetic Resonance, I elucidated the structure of one such factor, 2-methyl-4-hydroxyquinoline (MHQ). MHQ inhibits the activity of Type IV Pili (TFP) and that TFP targeting can explain its dispersal activity. My work thus identifies surface dispersal as a new activity of P. aeruginosa-produced small molecules, characterizes MHQ as a promising dispersal agent, and establishes TFP inhibition as a viable mechanism for P. aeruginosa dispersal. Additionally, I investigated three virulence factors (pyocyanin production, biofilm formation, and twitching motility) in a collection of 22 clinical isolates from blood stream infections. Despite the fact that all these isolates caused diseases and came from the same body site of different patients, they show large range in the traditional lab virulence assays. To determine the reasons for this variability, we investigated the genomes of the isolates using whole genome sequencing. We found that the majority of genes responsible for these virulence phenotypes were highly conserved among the isolates despite their phenotypic variability. Our work thus underscores the fact that lab virulence assays and genomic analysis may not be enough to predict what causes disease in the host and other factors may be needed to fully predict what will lead to disease.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog:
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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