Siderophore-Mediated Virulence and its Inhibition in Pseudomonas aeruginosa
| dc.contributor.advisor | Kirienko, Natalia V | en_US |
| dc.creator | Kang, Donghoon | en_US |
| dc.date.accessioned | 2024-01-24T21:49:59Z | en_US |
| dc.date.available | 2024-01-24T21:49:59Z | en_US |
| dc.date.created | 2023-12 | en_US |
| dc.date.issued | 2023-11-03 | en_US |
| dc.date.submitted | December 2023 | en_US |
| dc.date.updated | 2024-01-24T21:49:59Z | en_US |
| dc.description.abstract | Pseudomonas aeruginosa is a Gram-negative, nosocomial pathogen that causes life-threatening, acute infections in immunocompromised patients in intensive care units and debilitating chronic infections in those with cystic fibrosis. The rising prevalence of drug-resistant P. aeruginosa demands the exploration of new therapeutic avenues such as targeting pathogen virulence factors through small molecule inhibitors (‘antivirulents’). One key virulence factor for P. aeruginosa is the siderophore pyoverdine, which not only provides the bacterium with iron during infection, but also regulates the production of several secreted toxins, including the translational inhibitor exotoxin A and protease PrpL. We have further developed various in vivo and in vitro pathosystems using Caenorhabditis elegans, murine alveolar macrophages, and human bronchial epithelial cells to model P. aeruginosa pathogenesis and discovered several novel mechanisms of pyoverdine-dependent virulence. Against the nematode host, pyoverdine directly exerted virulence by translocating into host tissue and disrupting iron and mitochondrial homeostasis. Against mammalian cells, pyoverdine promoted the production of highly cytotoxic rhamnolipids. Due to a combination of these functions, pyoverdine production was necessary for P. aeruginosa virulence during acute murine lung infection. We also surveyed several panels of P. aeruginosa clinical isolates and demonstrated that pyoverdine production strongly correlated with pathogen virulence. Importantly, these models allowed us to characterize several novel small molecules that target either pyoverdine biosynthesis or function. In all aforementioned pathosystems, including murine lung infection, 5-FC curtailed pyoverdine production and significantly mitigated pathogenesis without overtly affecting bacterial titer, consistent with an antivirulent mechanism of action. Importantly, 5-FC was an effective therapeutic against not only laboratory-adapted strains of P. aeruginosa, but also highly virulent clinical isolates. 5-FC also synergized with the antipseudomonal agent gallium nitrate to inhibit bacterial growth without substantially increasing its own selective pressure for resistance. Moreover, from a small molecule diversity library screen, we identified compounds that directly interacted with the siderophore, attenuated the production of pyoverdine-regulated virulence factors (exotoxin A and protease PrpL), and rescued C. elegans during pathogen exposure. Altogether, findings in this dissertation demonstrate the promise of antivirulence therapeutics, specifically those that target pyoverdine, in treating multidrug-resistant P. aeruginosa infections. | en_US |
| dc.format.mimetype | application/pdf | en_US |
| dc.identifier.citation | Kang, Donghoon. "Siderophore-Mediated Virulence and its Inhibition in Pseudomonas aeruginosa." (2023). PhD diss., Rice University. https://hdl.handle.net/1911/115399 | en_US |
| dc.identifier.uri | https://hdl.handle.net/1911/115399 | en_US |
| dc.language.iso | eng | en_US |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | en_US |
| dc.subject | Pseudomonas aeruginosa | en_US |
| dc.subject | Siderophores | en_US |
| dc.subject | Virulence | en_US |
| dc.subject | Antivirulents | en_US |
| dc.title | Siderophore-Mediated Virulence and its Inhibition in Pseudomonas aeruginosa | en_US |
| dc.type | Thesis | en_US |
| dc.type.material | Text | en_US |
| thesis.degree.department | Biochemistry and Cell Biology | en_US |
| thesis.degree.discipline | Natural Sciences | en_US |
| thesis.degree.grantor | Rice University | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy | en_US |
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