Understanding bacterial resistance to therapeutic phage cocktails in an animal model of infection

了解感染动物模型中细菌对治疗性噬菌体混合物的耐药性

• 批准号: 2885581
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2885581
• 关键词: Understanding; bacterial; resistance; therapeutic; phage

The research is on bacteriophage (phage), viruses that specifically infect and kill bacterial cells, making phage therapy an exciting option to treat bacterial infections. With the growing threat of antibiotic resistance, there is considerable commercial and academic investment in phage therapy but hurdles still exist to its successful application in both humans and animals. While there has been incredible progress in understanding how bacteria resist phage predation under laboratory conditions, the importance of these processes during actual infections is unknown. This knowledge is critical to selection of phage in therapeutic cocktails that can work together to counter these bacterial defence systems. Our grouping has worked on the pathogenesis of Escherichia coli for over twenty years, understanding how specific strains cause different types of infection and we are now applying this knowledge to development of phage therapy which requires studying the interaction of phage with their target bacteria in the host during infection. The major focus of the research will be how the globally disseminated multi-drug resistant E. coli ST 131 resists phage treatment while infecting the mammalian bladder, and the work will build on three years of laboratory data including interactions in artificial urine. A key aspect of the project will be the application of a pig model of urinary tract infection in which the dynamics of phage predation and bacterial resistance can be studied. The PhD is 50% funded by Proteon Pharmaceuticals and they bring a wealth of expertise in phage therapy development to the research. We anticipate that the research will involve expression and sequence analysis of bacterial populations recovering from phage predation with a central theme of needing to understand bacterial population heterogeneity in the host during infection to select the most effective phage combinations. This work will run alongside other funded research developing phage interventions for UTI infections in dogs and E. coli O157 in the gastrointestinal tract of cattle. This project will benefit from world class facilities on campus including the Large Animal Research and Imaging Facility (LARIF) and the knowledge and resources provided by Proteon Pharmaceuticals, which has a platform to develop and commercialize phage-based products for animal and human health.

这项研究是关于噬菌体（噬菌体）的，噬菌体是一种专门感染和杀死细菌细胞的病毒，使噬菌体疗法成为治疗细菌感染的一种令人兴奋的选择。随着抗生素耐药性的威胁日益严重，在噬菌体治疗方面有相当大的商业和学术投资，但其在人类和动物中的成功应用仍然存在障碍。虽然在了解细菌如何在实验室条件下抵抗噬菌体捕食方面取得了令人难以置信的进展，但这些过程在实际感染中的重要性尚不清楚。这一知识对于选择治疗鸡尾酒中的噬菌体至关重要，这些噬菌体可以共同对抗这些细菌防御系统。我们的小组已经在大肠杆菌的发病机制上工作了二十多年，了解特定菌株如何引起不同类型的感染，我们现在正在将这些知识应用于噬菌体治疗的开发，这需要研究噬菌体与感染期间宿主中靶细菌的相互作用。研究的主要焦点是全球传播的多药耐药大肠杆菌是如何传播的。大肠杆菌ST 131在感染哺乳动物膀胱的同时抵抗噬菌体处理，这项工作将建立在三年的实验室数据基础上，包括在人工尿液中的相互作用。该项目的一个关键方面将是应用猪尿路感染模型，其中可以研究噬菌体捕食和细菌耐药性的动力学。该博士学位由Proteon Pharmaceuticals资助50%，他们为研究带来了丰富的噬菌体治疗开发专业知识。我们预计，该研究将涉及从噬菌体捕食中恢复的细菌群体的表达和序列分析，其中心主题是需要了解感染期间宿主中的细菌群体异质性，以选择最有效的噬菌体组合。这项工作将与其他资助的研究一起进行，这些研究开发了用于狗和大肠杆菌UTI感染的噬菌体干预措施。大肠杆菌O157在牛胃肠道中的表达。该项目将受益于校园内的世界一流设施，包括大型动物研究和成像设施（LARIF）以及Proteon Pharmaceuticals提供的知识和资源，Proteon Pharmaceuticals拥有开发和商业化用于动物和人类健康的噬菌体产品的平台。