Mechanistic insights into bacteriophage properties required for enhanced therapeutic potential at mucosal surfaces

增强粘膜表面治疗潜力所需的噬菌体特性的机制见解

基本信息

批准号：
10583463
负责人：
ANTHONY W MARESSO
金额：
$ 54.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583463
关键词：
Acute Address Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Bacterial Model Bacteriophages Binding Biological Biological Availability Biology Biomimetics Cells Chronic Disease Clinical Clinical Treatment Collection Communities Complex Creativeness Cytolysis Data Dedications Development Disease Drug resistance Ecosystem Elements Environment Epithelial Cells Equilibrium Etiology Focal Infection Foundations Genes Guidelines Health Human Infection Inflammation Influentials Integration Host Factors Invaded Knowledge Lead Life Life Cycle Stages Lytic Maintenance Malignant Neoplasms Medical center Medicine Microbiology Modern Medicine Molecular Mucous Membrane Mucous body substance Multi-Drug Resistance Nature Obesity Pathway interactions Persons Planet Earth Prevention Production Program Description Property Proteins Research Resistance Sampling Site Surface System Systemic infection Therapeutic Therapeutic Uses Tissue Sample Tissues Virus Work bacterial community clinically relevant college combat design efficacy testing genetic element human tissue infection risk insight member microbial community microbiome microbiota novel pathobiont pathogen prevent programs repository solute sugar synergism trait transmission process vaccine development

Acute Address Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Bacterial Model Bacteriophages Binding Biological Biological Availability Biology Biomimetics Cells Chronic Disease Clinical Clinical Treatment Collection Communities Complex Creativeness Cytolysis Data Dedications Development Disease Drug resistance Ecosystem Elements Environment Epithelial Cells Equilibrium Etiology Focal Infection Foundations Genes Guidelines Health Human Infection Inflammation Influentials Integration Host Factors Invaded Knowledge Lead Life Life Cycle Stages Lytic Maintenance Malignant Neoplasms Medical center Medicine Microbiology Modern Medicine Molecular Mucous Membrane Mucous body substance Multi-Drug Resistance Nature Obesity Pathway interactions Persons Planet Earth Prevention Production Program Description Property Proteins Research Resistance Sampling Site Surface System Systemic infection Therapeutic Therapeutic Uses Tissue Sample Tissues Virus Work bacterial community clinically relevant college combat design efficacy testing genetic element human tissue infection risk insight member microbial community microbiome microbiota novel pathobiont pathogen prevent programs repository solute sugar synergism trait transmission process vaccine development

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项目摘要

Project Summary The human mucosal surface is a complex ecosystem made of bacteria, viruses, epithelial cells, mucus, and molecules such as proteins, sugars, and other solutes whose balance is key to the health of the host. It is also the first line of defense against invading bacteria, and a site of colonization by diverse microbiota. Some members of this microbiota, termed pathobionts, cause serious local and systemic infections. However, the use of antibiotics to treat these infections is a classic Catch-22; there may temporary relief but down the road the very solution generates a bigger version of the original problem. Whereas one may rid the environment of the pathobiont, one also eliminates the beneficial microbiota that antagonize the pathobiont while creating a selection that further increases rates of resistance. In addition, the destruction of the balance of the ecosystem further predisposes that system to invasion by other pathobionts, and, in the long run, increases the risk of infection and inflammation. There is a real need to develop an alternative line of antibacterials that lack these limitations. The overall objective of this project is to discover bacteriophage, viruses that infect and kill bacteria, that are specifically active against drug-resistant pathobionts in the complex environment of a human mucosal surface. These phage should be specific for their bacterial target, as well as have evolved features that promote enhanced activity in the face of the complexity presented by such surfaces. Furthermore, should the pathobiont spread systemically, these phage should synergize with conventional antibiotics while simultaneously generating a steep evolutionary path for the emergence of new resistance. Using one of the world’s largest collections of therapeutic phages and characterizing them for enhanced activity in human mucosal biomimetics, the research program described here lays the foundation for the development of a novel class of mucosal-active antibacterials that clear problematic pathobionts while simultaneously maintaining balance of the native microbiota.

项目摘要人粘膜表面是一个由细菌，病毒，上皮细胞制成的复杂生态系统，粘液以及蛋白质，糖和其他溶剂等分子，它们的平衡是关键的主人的健康。它也是针对入侵细菌的第一道防线，也是多种微生物群定植。该微生物群的一些成员称为病原体，引起严重的本地感染和全身感染。但是，使用抗生素治疗这些感染是经典的捕获22；可能会暂时缓解，但在路上是解决方案生成更大的原始问题的版本。而人们可能会骑环境 Pathobiont，也消除了拮抗病原体的有益微生物群创建一个进一步提高阻力速率的选择。另外，破坏了生态系统的平衡进一步使该系统侵犯了其他病原体，并且从长远来看，增加了感染和感染的风险。真正需要发展缺乏这些局限性的抗菌替代线。该项目的总体目的是发现噬菌体，感染和杀死的病毒细菌，这些细菌特异性地针对复合物中的耐药病原体有效人粘膜表面的环境。这些噬菌体应该特定于它们的细菌目标，以及进化的特征，可以促进面对面的活动这种表面提出的复杂性。此外，病原体应该扩散从系统上，这些噬菌体应与常规抗生素协同作用，同时生成钢的进化路径，以实现新的抗性的出现。使用其中之一世界上最大的治疗噬菌体收集，并将其表征为增强活动在人类粘膜仿生学中，这里描述的研究计划为开发一类新的粘膜活性抗菌物，这些抗菌剂清除有问题的病原体同时维持天然微生物群的平衡。