Development of bacteriophages as alternatives to antibiotics

开发噬菌体作为抗生素的替代品

• 批准号: RGPIN-2018-04355
• 负责人: Dennis, Jonathan
• 金额: $ 2.62万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712953
• 关键词: Development; bacteriophages; alternatives; antibiotics

Bacteriophages (or phages) are viruses that specifically infect and kill bacteria. Most phages are comprised of an icosahedral head containing a double-stranded DNA genome, attached to a phage tail responsible for adhering to a surface receptor on the host bacterium. During infection the phage genome is delivered to the cell interior where phage proteins are expressed. The phage tail / host cell receptor interface is thought to be one of the most specific “lock and key” interactions in the biological world, and gives phages their exquisite specificity for bacterial cells. Molecular analysis of these mechanisms can provide insight into how phages defeat their bacterial hosts, and suggest successful strategies man can utilize to combat pathogenic bacteria. With the worldwide overuse of chemical antibiotics since the mid-20th century, we have recently observed a rapid increase in the number of bacteria presenting extreme antibiotic resistance, including bacteria of the genera Burkholderia and Stenotrophomonas. Therefore, the search for alternatives to antibiotics has gained importance, and the application of or treatment with phages has demonstrated promise, not only for human infections, but also for animal and plant diseases caused by bacteria. Numerous experimental studies have established phage treatment efficacy in both agricultural and clinical settings, and recently, instances of human lives being saved from pathogenic bacteria has been documented in North America. These results suggest that with further development, phages will become a useful addition to medicines available to complement or replace traditional antibiotics. The objective of this proposal is to examine phage mechanisms of attachment to bacterial receptors, and with this knowledge, optimize phages for application against highly antibiotic resistant bacteria. To decrease the evolution of phage resistance, multiple phages with different receptors will be combined, and phages that target virulence factors will promote anti-virulence in bacteria mutating to escape phage attack. Phages can be modified using molecular biology to eliminate problematic genes / proteins, and improved by adding genes that encode proteins that enhance activity (e.g. broaden host range, penetrate biofilms). Molecular characterization of the phage receptor-binding proteins, and the bacterium's surface receptors will provide important insights into the nature of the mechanisms involved in phage:bacterium interactions. The knowledge gained through this work will create opportunities to engineer phages against pathogenic and antibiotic resistant bacteria for a variety of novel biotechnological applications, including biosensors, relevant to agriculture, industry, and healthcare.

噬菌体(或称噬菌体)是专门感染和杀死细菌的病毒。大多数噬菌体由一个含有双链DNA基因组的二十面体头部组成，附着在负责附着在宿主细菌表面受体上的噬菌体尾部。在感染期间，噬菌体基因组被运送到细胞内部，在那里表达噬菌体蛋白。噬菌体尾部/宿主细胞受体界面被认为是生物界中最特异的“锁和钥匙”相互作用之一，并赋予噬菌体对细菌细胞的精致专一性。对这些机制的分子分析可以深入了解噬菌体是如何击败细菌宿主的，并提出人类可以用来对抗病原体的成功策略。 自20世纪中叶以来，随着化学抗生素在世界范围内的过度使用，我们最近观察到表现出极端抗生素耐药性的细菌数量迅速增加，包括伯克霍尔德氏菌属和斯氏营养单胞菌属。因此，寻找抗生素的替代品变得越来越重要，噬菌体的应用或治疗已经显示出前景，不仅对人类感染，而且对细菌引起的动植物疾病也是如此。许多实验研究已经确定了在农业和临床环境中的噬菌体治疗效果，最近，在北美记录了从病原菌中拯救人类生命的例子。这些结果表明，随着进一步的发展，噬菌体将成为可用于补充或取代传统抗生素的药物的有用添加剂。 这项建议的目的是检查噬菌体与细菌受体的结合机制，并利用这一知识，优化噬菌体应用于对抗高度耐药细菌的应用。为了减少噬菌体抗性的进化，具有不同受体的多个噬菌体将结合在一起，针对毒力因子的噬菌体将促进细菌为逃避噬菌体攻击而突变的抗毒力。可以使用分子生物学来修饰噬菌体，以消除有问题的基因/蛋白质，并通过添加编码增强活性的蛋白质的基因来改进噬菌体(例如，扩大宿主范围，穿透生物膜)。噬菌体受体结合蛋白和细菌表面受体的分子特征将为了解噬菌体参与细菌相互作用的机制的性质提供重要的见解。通过这项工作获得的知识将创造机会，为各种新的生物技术应用创造机会，包括与农业、工业和医疗保健相关的生物传感器。