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

这项研究针对的是噬菌体(Phage)，这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令人兴奋的选择。随着抗生素耐药性的威胁越来越大，在噬菌体疗法上有相当大的商业和学术投资，但它在人类和动物上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过程中的重要性尚不清楚。这一知识对于在治疗性鸡尾酒中选择噬菌体至关重要，这些噬菌体可以共同作用来对抗这些细菌防御系统。我们小组对大肠杆菌的发病机制进行了20多年的研究，了解了特定菌株如何导致不同类型的感染，我们现在正在将这些知识应用于噬菌体疗法的开发，这需要研究感染期间噬菌体与宿主中目标细菌的相互作用。这项研究的主要重点将是全球传播的耐多药大肠杆菌ST 131在感染哺乳动物膀胱时如何抵抗噬菌体治疗，这项工作将基于三年的实验室数据，包括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的尿路感染模型，在该模型中可以研究噬菌体捕食和细菌耐药性的动力学。Proteon制药公司为该博士提供了50%的资金，他们为这项研究带来了丰富的噬菌体疗法开发专业知识。我们预计这项研究将涉及从噬菌体捕食中恢复的细菌种群的表达和序列分析，其中心主题是需要了解感染期间宿主中的细菌种群异质性，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，开发针对狗的UTI感染和牛胃肠道的O157大肠杆菌感染的噬菌体干预措施。该项目将受益于校园内的世界级设施，包括大型动物研究和成像设施(LARIF)以及Proteon PharmPharmticals提供的知识和资源，Proteon PharmPharmticals拥有开发和商业化基于噬菌体的动物和人类健康产品的平台。

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.