Marine peptides as templates for the design of novel antimicrobials

食源性疾病和抗菌素耐药性等食品安全危害是威胁生命和紧迫的全球健康问题。鉴于人类和动物健康面临的挑战的复杂性，再加上对环境的影响，提高新型抗菌剂的有效性至关重要。大自然是这些高价值化合物的储藏库。具体地说，许多海洋衍生化合物已被证明具有抗菌性能。在上一期中，我们揭示了未开发的海洋物种、渔业废物和甲壳类副产品作为抗菌肽(AMPs)的潜在来源的潜力，而它们的作用模式尚未完全确定。现在似乎是开发新型抗菌剂的时机，这些抗菌剂获得抗药性的可能性较小，稳定，具有修饰或扩展的活性谱，且副作用有限。我的计划的基石是了解新型海洋AMP的作用机理，研究提高其效力的组合和条件，改善其抗菌性能，以期在食品生产中防止食品变质，并作为动物饲料和人类健康的抗生素替代品。*这一难题使我们有机会定义一个创新的计划，在分子水平上破译海洋新型AMP的结构-活性关系，从而识别参与其抗菌活性的关键残基。这一建议的一般假设是，结构-活性关系分析，使用集成的分子工程方法，将在稳定性和抗菌活性方面增强海洋AMPS的效力。具体目标将是：1)确定海洋AMPs及其类似物的一级结构或空间构象与抗菌活性之间的关系；2)研究海洋AMPs与细菌膜的相互作用；3)阐明海洋AMPs之间协同作用的分子机制，并研究它们的细菌膜泄漏潜力。*我们的研究活动将揭示导致生产具有有益性质的新型AMPs的策略，以满足公共卫生的优先需要。加拿大政府对抗菌素耐药性的反应载于2015年3月发布的《加拿大抗菌素耐药性和使用联邦行动计划》。有了这一行动计划，加拿大特别有能力促进研究工作，以解决抗菌素耐药性问题，以期在微生物和健康问题的前沿领域实现一个统一的全球目标。

Food safety hazards such as foodborne illnesses and antimicrobial resistance are life threatening and urgent global health problem. Given the complexity of the challenge faced at the interface of human and animal health, combined with the impact on the environment, it is crucial to increase the effectiveness of novel antimicrobial agents. Nature is a reservoir for these high-value compounds. Specifically, numerous marine-derived compounds have been proven to harbor antibacterial properties. In previous installment, we revealed the potential of untapped marine species, fishery wastes and crustaceans' by-products, as a promising source of antimicrobial peptides (AMPs), whilst their mode of action has not been entirely determined yet. The time appears opportune for the development of novel classes of antimicrobial agents with less likelihood to gain resistance, which are stable, have modified or extended spectrum of activity, and with limited side effects. The cornerstones of my program are the understanding of mechanisms of action of the novel marine AMPs, the study of combinations and conditions to enhance their potency, the improvement of their antibacterial properties for potential in food production to prevent food spoilage and as antibiotic alternatives in animal feed and human health. ******This conundrum gives us the opportunity to define an innovative program where the structure-activity relationships of marine novel AMPs can be deciphered at the molecular level which allows identifying the key residues involved in their antibacterial activity. The general hypothesis of this proposal is that structure-activity relationship assays, using an integrated molecular engineering approach, will enhance marine AMPs potency in terms of both stability and antimicrobial activity. The specific objectives will be: 1) To determine the relationship between the primary structure or spatial conformation and antimicrobial activity of marine AMPs, and analogues thereof; 2) To study the marine AMPs-bacterial membrane interaction; 3) To elucidate the molecular mechanisms of synergy between the marine AMPs and study their bacterial membrane leakage potential.******Our research activities will unravel the strategies leading to the production of novel AMPs with beneficial properties to encounter public health priority. Government of Canada's response to antimicrobial resistance is laid out in the Federal Action Plan on Antimicrobial resistance and Use in Canada, released in March 2015. With this Action Plan, Canada is particularly well positioned to promote efforts in research to address antimicrobial resistance toward a united global objective in frontiers of microbiological and health concerns.