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http://hdl.handle.net/11375/28498
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DC Field | Value | Language |
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dc.contributor.advisor | Wright, Gerard | - |
dc.contributor.author | Surette, Matthew | - |
dc.date.accessioned | 2023-05-03T19:14:32Z | - |
dc.date.available | 2023-05-03T19:14:32Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://hdl.handle.net/11375/28498 | - |
dc.description.abstract | Antibiotics are one of the most important advances in medical science, but today, antibiotic-resistant bacteria threaten this legacy. We risk losing our ability to treat acute infections, perform invasive surgeries, and exploit immunosuppressive therapies like transplantation and cancer chemotherapy. The antibiotics we use today have ancient roots and have been produced by microbial denizens of the soil for millions of years before we adopted them in the 20th century. This history has modern consequences, as strategies to resist these compounds have evolved in concert for millions of years. The result is a vast reservoir of antimicrobial resistance that exists in environmental bacteria, which have the potential to be mobilized into human pathogens and cripple our antibiotic arsenal. Here, I set out to deepen our understanding of the environmental resistome, focusing on the rifamycin antibiotics. These compounds inhibit bacterial RNA polymerase and are frontline agents for treating tuberculosis. Environmental bacteria from the phylum Actinobacteria induce the production of resistance enzymes in response to these compounds. Although mechanistic questions remain, we demonstrate that this induction stems from the inhibition of RNA polymerase by rifamycins. The induction process is known to require a specific DNA motif; here, I identify additional sequences as part of this motif and use this information to map inducible rifamycin resistance across the entire phylum. The most common rifamycin-inducible gene was an uncharacterized family of proteins annotated as DNA helicases. I investigated these proteins and discovered that they bind to RNA polymerase and displace rifamycin antibiotics, a novel mechanism of rifamycin resistance. Lastly, we repurposed this inducible system to develop an assay to screen for novel RNA polymerase inhibitors. From this screen, we identified a rifamycin immune to a common environmental resistance enzyme and a new family of rifamycin antibiotics. | en_US |
dc.language.iso | en | en_US |
dc.subject | Antibiotic Resistance | en_US |
dc.subject | Rifamycins | en_US |
dc.title | UNDERSTANDING AND OVERCOMING INDUCIBLE RIFAMYCIN RESISTANCE | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Biochemistry and Biomedical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
dc.description.layabstract | Our antibiotic arsenal consists primarily of metabolites produced by soil microbes, which humanity repurposed into life-saving medicines in the 20th century. As a direct result of the natural origin of antibiotics, resistant bacteria exist in these same environments, independent of human use. Individual genetic determinants from this reservoir can emerge in pathogenic bacteria without warning and render antibiotics ineffective. The aim of this work was to understand how environmental bacteria resist the rifamycin class of antibiotics. Firstly, I investigated the ability of some bacteria to sense the presence of rifamycins, and in response produce proteins to protect themselves. I discovered that this process requires specific DNA sequences nearby resistance genes. Using this DNA sequence as a guide I cataloged resistance genes in thousands of bacterial genomes and discovered a new mechanism of rifamycin resistance. Lastly, I exploited this rifamycin sensing system to discover new antibiotics from soil microbes. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Surette_Matthew_D_2023-04_PhD.pdf | 13.33 MB | Adobe PDF | View/Open |
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