UBC Theses and Dissertations
Comprehensive characterization of β-lactamase resistome Gholipour, Sevan
β-lactamases are enzymes capable of conferring pathogens with resistance against β-lactam antibiotics. They are widely disseminated in clinical pathogens via horizontal gene transfer, which raises major concerns in clinics. Interestingly, β-lactamases have evolved multiple times from distinct evolutionary origins, resulting in five diverse classes of enzymes. However, our current understanding of β-lactamase is almost entirely focused on clinically isolated enzymes, which may only be a small fraction of an even greater plethora of β-lactamase diversity in the environmental biosphere. This thesis aims to comprehensively study the distribution of β-lactamases, including the ones spread in environmental samples. The analysis of β-lactamases in public databases revealed the evolutionary origins of each class of β-lactamase by highlighting multiple convergent evolutionary events within the penicillin-binding protein-like and metallo-β-lactamase superfamilies. The phylogeny analyses of the superfamilies revealed new sequence clusters related to β-lactamases, providing a novel insight into the evolutionary ancestors of the enzyme superfamily. The subsequent bioinformatic analysis of metagenomic samples unveiled a vast pool of environmental enzymes that belong to the metallo-β-lactamase and serine β-lactamase families. The analysis of β-lactamases in the various ecosystems showed a larger fraction of resistant genes in wastewater samples, and yet, β-lactamases are widely spread in diverse environments. Overall, the results presented in this thesis contribute to our understanding of the β-lactamase family and will help to improve surveillance programs in the future.
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