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

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.

项目概要人体粘膜表面是一个由细菌、病毒、上皮细胞、粘液和分子，如蛋白质、糖和其他溶质，其平衡是维持生命活动的关键它也是宿主健康的第一道防线，也是细菌入侵的场所。该微生物群的一些成员被称为病原体，引起严重的局部和全身感染，但是可以使用抗生素来治疗这些感染。感染是典型的第二十二条军规；可能会暂时缓解，但最终的解决方案是生成原始问题的更大版本。病原体，同时还消除了拮抗病原体的有益微生物群创造一个进一步增加抵抗率的选择。进一步生态系统的平衡使该系统容易受到其他病原体的入侵，并且，从长远来看，会增加感染和炎症的风险，因此确实需要发展。没有这些限制的另一种抗菌药物。该项目的总体目标是发现噬菌体，即感染和杀死细菌的病毒细菌，对复合物中的耐药病原体具有特异性活性这些噬菌体应该对其细菌具有特异性。目标，以及进化的特征，促进增强活动面对此外，这种表面呈现出复杂性。从系统角度来看，这些噬菌体应与常规抗生素产生协同作用，同时使用其中一种方法为新耐药性的出现形成一条陡峭的进化路径。世界上最大的治疗性噬菌体集合并对其进行表征以增强活性在人类粘膜仿生学中，这里描述的研究计划为开发一类新型粘膜活性抗菌剂，可清除有问题的病原体同时保持天然微生物群的平衡。