Marine peptides as templates for the design of novel antimicrobials

海洋肽作为新型抗菌药物设计的模板

• 批准号: RGPIN-2019-06076
• 负责人: Beaulieu, Lucie
• 金额: $ 2.91万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765361
• 关键词: Marine; peptides; templates; design; novel

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.

食源性疾病和抗生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，以及对环境的影响，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。具体而言，许多海洋衍生化合物已被证明具有抗菌特性。在上一期中，我们揭示了未开发的海洋物种，渔业废物和甲壳类动物的副产品，作为一个有前途的来源抗菌肽（AMP）的潜力，虽然他们的作用方式尚未完全确定。现在似乎是开发新型抗菌剂的适当时机，这些抗菌剂不易产生耐药性，稳定，具有改良或扩展的活性谱，副作用有限。我的计划的基石是了解新型海洋AMP的作用机制，研究增强其效力的组合和条件，改善其抗菌特性，以防止食品腐败，并作为动物饲料和人类健康中的抗生素替代品。 这一难题使我们有机会定义一个创新的计划，其中海洋新型抗菌肽的结构-活性关系可以在分子水平上破译，从而可以识别参与其抗菌活性的关键残基。该建议的一般假设是，使用综合分子工程方法的结构-活性关系测定将增强海洋AMP在稳定性和抗微生物活性方面的效力。具体目标是：1）确定海洋抗菌肽及其类似物的一级结构或空间构象与抗菌活性的关系; 2）研究海洋抗菌肽与细菌膜的相互作用; 3）阐明海洋抗菌肽之间协同作用的分子机制并研究其细菌膜渗漏潜力。我们的研究活动将揭示导致生产具有有益特性的新型AMP的策略，以满足公共卫生优先事项。加拿大政府对抗菌素耐药性的应对措施载于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》。有了这项行动计划，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，实现微生物和健康问题前沿的统一全球目标。