Using C. elegans to Identify Novel Targets Against Multidrug-Resistant Bacteria

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dc.contributor.advisorKirienko, Natashaen_US
dc.contributor.advisorTao, Janeen_US
dc.creatorHummell, Nicholas Andrewen_US
dc.date.accessioned2020-07-06T19:48:51Zen_US
dc.date.available2021-12-01T06:01:09Zen_US
dc.date.created2020-12en_US
dc.date.issued2020-07-06en_US
dc.date.submittedDecember 2020en_US
dc.date.updated2020-07-06T19:48:53Zen_US
dc.description.abstractAntibiotic-resistant infections cause an average of 23,000 deaths per year. Due to dwindling commercial interest for antimicrobial discovery, novel methods for combating infection and developing new antimicrobials are desperately needed. Previously in our lab, we performed a high-throughput chemical screen to identify small molecules that rescued the nematode Caenorhabditis elegans from infection by P. aeruginosa. Of the hits identified, 5 (LK32, LK34, LK35, LK38 and LK56) were determined to be stimulators of host defense pathways while 5 additional hits (DMAQ-B1, CD437, carboplatin, oxaliplatin, and PSB-069) possessed a known target or bioactivity but had no previously reported antimicrobial activity against P. aeruginosa.. Using microarray analysis, RNAi knockdown of candidate pathways, transgene reporters, and infection assays with other pathogens, we made important observations concerning the mechanism of action and therapeutic repurposing potential for the compounds. Firstly, I identified a subunit of the Mediator complex, mdt-15, and the PMK-1/p38 MAPK pathway as necessary for rescue for LK56 and LK38 respectively, demonstrating that both pathways are amenable to immune stimulation. I have also found that some molecules can defend against E. faecalis and S. aureus as well as Pseudomonas while being largely non-toxic. Additionally, most molecules stimulated the activation of multiple innate immune pathways. These experiments showed the potential for development of broad-spectrum immune stimulants and identified promising pathways amenable to immune stimulation. They also highlighted potential for our LK molecules as tools for future studies of innate immune stimulation in C. elegans. For our bioactive compounds, I used similar C. elegans-based methods to generate a number of important conclusions: I confirmed the antimicrobial activity of CD437 against Gram-positive pathogens, observed a weakness of P. aeruginosa to platinum complexes, and established the naturally occurring insulin mimetic, DMAQ-B1, as a powerful antimicrobial agent. Although toxic, an existing non-toxic analog presents potential for further therapeutic optimization. Through these studies, I have utilized C. elegans as a powerful drug discovery tool to gain insight into mechanism and therapeutic utility of two groups of anti-infective molecules. I have shown the strength of our model in drug repurposing efforts as well as demonstrated therapeutic potential for immune stimulation as a promising approach to combatting the growing antimicrobial resistance crisis.en_US
dc.embargo.terms2021-12-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationHummell, Nicholas Andrew. "Using C. elegans to Identify Novel Targets Against Multidrug-Resistant Bacteria." (2020) Diss., Rice University. <a href="https://hdl.handle.net/1911/108831">https://hdl.handle.net/1911/108831</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/108831en_US
dc.language.isoengen_US
dc.rightsCopyright 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.subjectC. elegansen_US
dc.subjectDrug discoveryen_US
dc.subjectImmune stimulationen_US
dc.subjectRepurposingen_US
dc.subjectAntimicrobial Resistanceen_US
dc.titleUsing C. elegans to Identify Novel Targets Against Multidrug-Resistant Bacteriaen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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