Browsing by Author "Gregson, Daniel"

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    A Genomic and Proteomic Survey of Traits that Modulate Antimicrobial Resistance in Staphylococcus aureus
    (2024-04-18) MacKenzie, Colin Campbell; Lewis, Ian; Gregson, Daniel; Turner, Raymond
    Antibiotic resistance is a growing global public health crisis which threatens to remove our primary treatment against bacterial infections. The mechanisms of antibiotic resistance in bacterial pathogens have been extensively studied, however questions surrounding the regulatory mechanisms of these resistance factors in clinical isolates are yet to be answered. In collaboration with the Broad Institute of MIT and Harvard, The Harvard T.H. Chan School of Public Health, and Alberta Precision Laboratories we completed whole-genome sequencing on 7,997 Staphylococcus aureus genomes from a larger study cohort of over 38,000 blood stream infections over a 16-year period. In addition to whole-genome sequencing, the proteomes of the bacterial isolates were quantitatively assessed using Tandem Mass Tag (TMT) ultra-high-performance liquid chromatography mass-spectrometry (UHPLC-MS) methods. Changes in protein levels and growth in the bacterial isolates are related to the variability in the genetic composition of the resistance operons of the specific clinical strains. This study has resulted in the understanding of a complex coregulatory interaction between two resistance operons of Methicillin Resistant S. aureus related to the mecA and blaZ resistance factors. Further, to better understand the metabolic adaptations of pathogens under antibiotic exposure, kinetic flux profiling of Escherichia coli metabolism under various antibiotic stressors was completed through the addition of fully labelled 13C-glucose. This intracellular flux monitoring via UHPLC-MS analysis, at a scale of seconds, has been used to gain insight into the metabolic alterations within E. coli metabolism under the exposure to twelve antibiotics spanning three common classes of antibiotics: DNA synthesis inhibitors, protein synthesis inhibitors, and cell wall synthesis inhibitors. This study has resulted in the classification of important metabolic adaptations occurring because of specific antibiotic compounds. Further, this intracellular metabolic study has shown evidence of a previously unexpected mevalonate pathway in E. coli. These studies have provided insight into the dynamics of pathogen interactions with antibiotics, and a deeper understanding of the antibiotic resistance mechanisms existing in pathogenic strains.
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    Clinical Epidemiology and Precision Diagnostics for a Regionwide Cohort of Bloodstream Infections
    (2023-05-08) Mansuri, Alikhan; Lewis, Ian; Gregson, Daniel; Prenner, Elmar
    Bloodstream infections (BSIs) pose considerable morbidity for patients including progression to septic shock, a life-compromising disease with 30% mortality rate at 30 days from the onset of infection. During my MSc, I have advanced the idea of Precision Infection Management (PIM) as a novel treatment strategy that accounts for microbial virulence alongside host factors for improving mortality rates from BSIs. To lay the foundation for PIM, I conducted two investigations on a 14-year BSI cohort obtained from the Calgary Health Zone. My first objective was to systematically assess the impact of growing antimicrobial resistance on patient mortality trends. I uncovered increasing resistance rates across multiple first-line drugs, including E. coli resistance for ceftriaxone (binomial test p < 0.05). Despite this, E. coli mortality rates remained remarkably stable through the study period (linear model R2 = 0.2). While encouraging, 30-day mortality rates were worryingly high for some species, trending upwards of 30%, furthering a need for the PIM clinical strategy for reducing burden of disease. To address this, I identified microbial virulence factors that could be tested for in the diagnosis of BSIs. I leveraged a cohort of >600 E. faecium isolates and linked microbial proteomic profiles with patient 30-day mortality using Cox proportional hazard and log-rank tests. I identified arcB_1 expression as being significantly associated with 5035 days decreased survival through a 30-day window (adjusted log rank p = 0.0078). While preliminary, this finding is an exciting proof of principle for PIM and implicates virulence-directed therapy as a feasible and promising new treatment avenue that could reduce 30-day mortality.
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    Discordant Diagnosis of Malaria in a Family of Child Refugees from Sierra Leone
    (2013-01-01) Yanow, Stephanie K; Gregson, Daniel; Chawla, Rupesh
    The clinical presentation and diagnosis of malaria involving a family with seven children who arrived in Canada as refugees is reported. Discrepancies in front-line testing using microscopy and rapid diagnostic tests compared with confirmatory testing using real-time polymerase chain reaction in this cluster of symptomatic and asymptomatic patients were identified.