Genome-guided Discovery of Bacteriocins

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The explosion of genomic data and development of innovative bioinformatics tools have revolutionized natural product research. This proposal aims to leverage the vast amount of microbial genomic data by taking advantage of recent advances in bioinformatics to search for bacteriocins. Bacteriocins are antimicrobial peptides produced by bacteria to kill other bacteria. They are mainly used in food and animal industries as natural preservatives or antimicrobial agents. Recently, their role in regulating gut microbiota revealed their importance in promoting human health. They are also considered as promising alternatives or adjuncts to traditional antimicrobials. Thus, my program is very timely and important, as the increasing prevalence of antimicrobial resistance has called for increased efforts to discover novel antimicrobial compounds for the food, agriculture, and health sectors. The main objective of this research program is to identify and characterize new bacteriocins through genome mining, specifically head-to-tail cyclized and leaderless bacteriocins. Head-to-tail cyclized bacteriocins are circular peptides and their cyclic nature confers remarkable peptide stability. Leaderless bacteriocins are unique because unlike other bacteriocin classes, they do not require any structural modifications to be active, which simplifies their bioproduction. The search will initially be directed towards these 2 bacteriocin classes, but in the longer term, we will expand to encompass other under-investigated classes. Positive outcomes of this program will establish innovative ways of prioritizing target bacteriocins that maximize the probability of successful molecule discovery, approaches that will be useful for future investigations of other underexplored bacteriocin classes. Short-term (5-yr) objectives include detailed in silico identification and analysis of putative bacteriocins, and purification and characterization of novel peptides. We will study the structural properties and bioactivities of target peptides, and investigate their modes of action. This work will provide the foundational knowledge required to direct implementation of the use of the characterized peptides as biopreservatives and/or as therapeutic agents. Moreover, the structure-activity studies will guide future bioengineering efforts to design compounds with desired properties. This program involves interdisciplinary fields (i.e., biochemistry, analytical chemistry, molecular biology, microbiology, and bioinformatics), exposing students to various tools employed in a modern natural products laboratory. My students develop strong communication, leadership, and scientific research skills, providing them with transferable skills and exceptional preparation for a future career in biotechnological industries or in academia, and making them highly productive members of the Canadian scientific community.