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已经彻底改变了天然产物的研究。本提案旨在利用生物信息学的最新进展，利用大量的微生物基因组数据来寻找细菌素。细菌素是细菌产生的抗菌肽，用于杀死其他细菌。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体健康方面的重要性。它们也被认为是传统抗菌素的有希望的替代品或辅助物。因此，我的计划非常及时和重要，因为抗菌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素化合物。本研究计划的主要目的是通过基因组挖掘来鉴定和表征新的细菌素，特别是头尾环化和无领导的细菌素。从头到尾环化的细菌素是一种环状肽，其循环性质赋予了显著的肽稳定性。无领导细菌素是独一无二的，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。研究最初将针对这两类细菌素，但从长远来看，我们将扩大到包括其他尚未研究的细菌素。该计划的积极成果将建立创新的方法来优先考虑目标细菌素，从而最大限度地提高成功分子发现的可能性，这些方法将对未来研究其他未被开发的细菌素类有用。短期（5年）目标包括对假定的细菌素进行详细的计算机鉴定和分析，以及对新肽的纯化和表征。我们将研究目标肽的结构特性和生物活性，并研究它们的作用方式。这项工作将提供所需的基础知识，以直接实施使用特征肽作为生物防腐剂和/或治疗剂。此外，结构-活性研究将指导未来的生物工程努力设计具有所需性能的化合物。本课程涉及跨学科领域（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中使用的各种工具。我的学生培养了很强的沟通、领导能力和科研技能，为他们提供了可转移的技能，为他们未来在生物技术行业或学术界的职业生涯做好了特殊的准备，使他们成为加拿大科学界的高效成员。

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.