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Browsing by Author "Borlee, Brad, committee member"

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    Effects of drought stress on early white pine blister rust development in limber pine
    (Colorado State University. Libraries, 2022) Bertram, Jonathan H., author; Stewart, Jane E., advisor; Scoettle, Anna W., advisor; Borlee, Brad, committee member; Ocheltree, Troy, committee member
    Climate change and forest pathogens are expected to interact as incidences of drought increase and affect the disease triangle between hosts, pathogens, and the environment. Trees will become physiologically affected by drought stress and primary pathogens such as fungal biotrophs will experience drought stress as mediated through the host. White pine blister rust, caused by the non-native pathogen Cronartium ribicola, is a devastating fungal pathogen, and little is known about how it will perform (measured by fungal growth or disease severity) within pine hosts experiencing unusual drought. This study aimed to address some of the unknown aspects of this interaction by performing a greenhouse drought × pathogen experiment with Pinus flexilis seedlings, measuring host physiology, quantifying specific aspects of pathogen performance, and looking for interactive effects. Watering treatments consisting of well-watered, mild chronic drought, or severe acute drought were applied to 432 seedlings; after 3 months, a subset of 198 seedlings were inoculated with C. ribicola basidiospores under ideal inoculation conditions, after which watering treatments continued for a further 9 months. Specific rust performance measurements included mycelial growth via relative rust DNA quantification and ratings of disease severity by watering treatment.
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    From computation to communication: unveiling Salmonella metabolic plasticity and public perceptions of the microbial world using multi-omics and thematic analysis
    (Colorado State University. Libraries, 2024) Kokkinias, Katherine, author; Wrighton, Kelly C., advisor; Kelp, Nicole, committee member; Borlee, Brad, committee member; Weir, Tiffany, committee member
    Research and communication on microorganisms and microbiomes has become increasingly important in recent decades due to evolving threats posed by infectious diseases and microbial contributions to ecological systems. Antibiotic resistance presents a significant challenge to global health equity, with nontyphoidal Salmonella infections being a prominent concern. Despite its prevalence and impact, Salmonella infections lack effective vaccines, posing a serious threat to vulnerable populations. Concurrently, misconceptions and misinformation about microorganisms and microbiomes can arise given the dynamic nature of scientific research which can hinder effective science communication and health outcomes. Despite this, little is known about public perceptions of microorganisms and microbiomes, impeding our ability to create effective, tailored science messaging. Both basic pathogen research and science communication research are essential to identify targeted prevention strategies and to understand public perceptions of microorganism and microbiomes. This dissertation spans microbiome and science communication research, employing both qualitative and quantitative methods. The overarching research goals of this dissertation are to 1) lay the groundwork for therapeutics by studying Salmonella metabolism and metabolic plasticity, 2) develop a multi-omics repository to expand the usability of our omics datasets, and 3) understand public perceptions of microorganisms and microbiomes to improve future microbial science communication efforts. Chapter 1 as the introductory chapter reviews the current state of Salmonella and science communication research, providing a context for the new research presented in this dissertation. Through a multi-omics approach, Chapter 2 explores the metabolic strategies of Salmonella under different diet backgrounds and over time, offering insights into potential therapeutic targets. Chapter 3 introduces the CBA_DREAMM database, facilitating centralized storage and sharing of multi-omics datasets to enhance communication of our research and collaboration in microbiome research. Chapter 4 investigates public perceptions of microbes and microbiomes in the United States, revealing a need for tailored science communication efforts. Additionally, the study emphasizes the importance of clear communication, trust, and emotions, like apathy, in science communication. Chapter 5 is the conclusion, summarizing findings from Chapter 2, 3, and 4 and describing future directions. By bridging natural and social sciences, this dissertation aims to inform strategies for tackling global issues by advancing microbiome and science communication research.
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    Potentiation of beta-lactam antibiotics against Mycobacterium tuberculosis by 2-aminoimidazoles: investigation into the mechanism of action and its relevance to mycobacterial bioenergetics
    (Colorado State University. Libraries, 2017) Jeon, Albert Byungyun, author; Basaraba, Randall J., advisor; Borlee, Brad, committee member; Gustafson, Daniel, committee member; Jackson, Mary, committee member; Melander, Christian, committee member; Obregón-Henao, Andrés, committee member
    Tuberculosis, caused by Mycobacterium (M.) tuberculosis, is a global health problem still causing morbidity and mortality due in part to the emergence of drug-resistance and the lack of new antimicrobial agents to treat the disease. While infection with drug-sensitive M. tuberculosis has cure rates between 90-95% with the conventional multidrug-regimen comprised of four different first-line anti-tuberculosis drugs, administered for a minimum of 6 months. In the event where premature termination of the treatment or poor patient compliance occurs, the disease may progress into latent tuberculosis, which holds the risk of reoccurring disease or even leads to development of drug-resistant strains that are refractory to first line anti-tuberculosis drugs. This persistence is a major hurdle in global tuberculosis control and warrants the development of a new class of anti-tuberculosis drugs or novel strategies to target persisting bacilli. However, the current anti-tuberculosis drug pipeline does not suggest an immediate solution required for the successful control of global tuberculosis epidemic. In sum, there is an urgent need for a new strategy to complement current tuberculosis chemotherapy. 2-aminoimidazoles and their derivatives have been shown to be effective inhibitors of bacterial biofilms. Not only does this class of small molecules inhibit the formation of or disperse biofilms, but they also exhibit a clinically relevant feature of potentially abrogating antibiotic resistance in important pathogenic bacteria. From the studies characterizing persistent M. tuberculosis bacilli after anti-tuberculosis therapy in animal models, it has been suggested that this subpopulation of bacilli share similarities with bacterial biofilms. Our group developed an in vitro culture system where M. tuberculosis can be cultured in biofilm-like surface-attached communities with host-derived macromolecules and showed they express extensive drug-tolerance to one of the first-line anti-tuberculosis drug, isoniazid. Based on the previous effects of 2-aminoimidazoles on biofilms and drug-resistant bacteria, we hypothesized that 2-aminoimidazoles could reverse phenotypic drug-tolerance expressed by M. tuberculosis in our model and demonstrated that, indeed, derivatives of 2-aminoimidazoles effectively resensitized drug-tolerant bacilli to isoniazid. Additionally, a fortuitous but critical observation was made in which one of the potent 2-aminoimidazole derivatives potentiated the effect of ß-lactam antibiotics against M. tuberculosis. As repurposing ß-lactams in tuberculosis treatment regimen has potential therapeutic value, which are described throughout this dissertation. In chapter 2, 2-aminoimidazole compounds are shown to be effective at potentiating multiple ß-lactam antibiotics. Minimum inhibitory concentrations, as well as bactericidal concentrations, of ß-lactams were dramatically reduced when combined with 2-aminoimidazoles. Through a transcriptional analysis of M. tuberculosis treated with 2B8, one of our lead 2-aminoimidazoles induced cell envelope related stress responses and suppressed mycolic acid biosynthesis. Thereafter, it was hypothesized that 2-aminoimidazoles disrupts one or more factors conferring M. tuberculosis ß-lactam resistance, which we shown in chapter 3 is in large part due to a reduction in secretion of the enzyme ß-lactamase and by increasing cell envelope permeability. 2B8 treated M. tuberculosis exhibited significantly lower ß-lactamase activity in culture supernatant, which was due to a general protein secretion defect, and not from direct inhibition of ß-lactamase enzyme activity by 2-aminoimidazole compounds. As expected from the transcriptional analysis, 2B8 induced alterations in cell envelope lipid composition highlighted by the accumulation of trehalose monomycolate, the reduction of trehalose dimycolate, as well as a decrease in mycolic acid biosynthesis. Additionally, increased sensitivity to the detergent SDS, increased permeability to multiple nucleic acid staining dyes, and increased bindings of peptidoglycan-targeting antibiotics were observed when with 2B8 treatment. Based on major findings from chapter 3, it was hypothesized that the underlying mechanisms of 2-aminoimidazoles are the disruption of proton motive force and the disturbance of mycobacterial bioenergetics. In chapter 4, the collapse of proton motive force with additional dose-dependent block of mycobacterial electron transport chain is highlighted. Through a series of assays, we determined that 2B8 blocks the M. tuberculosis electron transport chain downstream of complex I and II, but upstream of complex IV. Taken together, these results collectively extend our current understanding of the various effects 2-aminoimidazole treatment has on M. tuberculosis susceptibility to ß-lactam antibiotics through perturbation of mycobacterial bioenergetics which can provide a profound impact in improving current tuberculosis therapy. Furthermore, this study offers valuable information for the construction of the next generation of potent 2-aminoimidazoles to improve efficacy against M. tuberculosis as well as other compounds that may be developed as a new anti-TB drug targeting bioenergetics.