Identifying cellular mechanisms of intrinsic antibiotic resistance in Klebsiella pneumoniae

Antimicrobial resistance is one of the primary rising public health concerns and is causing vast treatment limitations. At the top of the WHO bacterial priority pathogen list is multidrug resistant (MDR) Klebsiella pneumoniae, a generalist and opportunist primarily impacting immunocompromised and hospitalized individuals. Critically overlooked in K. pneumoniae is its intrinsic antibiotic resistance-the innate ability to evade antibiotics using its pre-existing metabolic pathways, instead of acquired resistance mechanisms driven by previous antibiotic exposure. Previous work in the Cameron Lab at the U of R applied genome-wide insertion sequencing to identify intrinsic resistance genes in a MDR K. pneumoniae clinical isolate (HUM 7199). My MSc research aims to elucidate the mechanisms by which environmental conditions can affect regulation of cellular metabolic pathways, resulting in altered cellular physiology and thus, increased antibiotic resistance. To do so, I will use K. pneumoniae HUM 7199 gene-knockout mutants developed during my Undergraduate Research Award (UGRA) and BSc Honours as a tool to untangle the cellular networks involved in conveying intrinsic antibiotic resistance. I will conduct mass spectrometry in collaboration with other researchers at the U of R to capture, quantify and identify proteins important for regulation of intrinsic resistance gene expression. Additionally, I will be conducting RNA sequencing to map how gene networks respond and rebalance cell physiology when these genes are knocked out. Because of the emphasis on acquired and evolved antibiotic resistance mechanisms in existent research, intrinsic resistance mechanisms are often overlooked but provide promising potential as novel antibiotic targets once their mechanisms are uncovered.