Genome-guided Discovery of Bacteriocins

基因组数据的爆炸和创新生物信息学工具的发展彻底改变了天然产物的研究。该提案旨在通过利用生物信息学的最新进展来利用大量的微生物基因组数据来搜索细菌素。细菌素是由细菌产生的杀死其他细菌的抗菌肽。它们主要用于食品和动物工业作为天然防腐剂或抗菌剂。最近，它们在调节肠道微生物群中的作用揭示了它们在促进人类健康方面的重要性。它们也被认为是传统抗菌剂的有前途的替代品或替代品。因此，我的计划是非常及时和重要的，因为抗生素耐药性的日益普遍要求加大努力，为食品，农业和卫生部门发现新的抗菌化合物。该研究计划的主要目标是通过基因组挖掘来识别和表征新的细菌素，特别是头到尾环化和无前导的细菌素。首尾环化的细菌素是环状肽，其环状性质赋予显著的肽稳定性。无前导细菌素是独特的，因为与其他细菌素类别不同，它们不需要任何结构修饰就能发挥活性，这简化了它们的生物生产。搜索最初将针对这2类细菌素，但从长远来看，我们将扩大到包括其他未充分研究的类别。该计划的积极成果将建立优先考虑目标细菌素的创新方法，最大限度地提高成功分子发现的可能性，这些方法将有助于未来对其他未充分探索的细菌素类的研究。 短期（5年）目标包括详细的计算机识别和分析推定的细菌素，纯化和表征的新肽。我们将研究目标肽的结构特性和生物活性，并探讨其作用模式。这项工作将提供所需的基础知识，以指导实施的使用的特征化的肽作为生物防腐剂和/或作为治疗剂。此外，结构-活性研究将指导未来的生物工程工作，以设计具有所需性质的化合物。该计划涉及跨学科领域（即，生物化学，分析化学，分子生物学，微生物学和生物信息学），让学生接触到现代天然产物实验室使用的各种工具。我的学生培养了很强的沟通，领导和科研技能，为他们提供了可转移的技能和特殊的准备，为未来的职业生涯在生物技术行业或学术界，并使他们成为加拿大科学界的高产成员。

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.