Antibiotics from nose and throat commensals that impact pathogen colonization

来自鼻子和喉咙共生体的抗生素会影响病原体定植

基本信息

批准号：
8534026
负责人：
MICHAEL ANDREW FISCHBACH
金额：
$ 41.47万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-20 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534026
关键词：
Actinobacteria class Adolescence Adult Age Anterior nares Antibiotics Bacteria Base Sequence Bioinformatics Biological Assay Chemicals Child Childhood Clinical Coculture Techniques Communities Corynebacterium Data Epidemiologic Studies Fractionation Funding Genes Genetic Genus staphylococcus Growth Health Human Human Development Human Microbiome Individual Infection Life Mediating Metagenomics Microbe Nose Pharyngeal structure Probiotics Production Propionibacterium Proteobacteria Research Risk Role Sampling School-Age Population Series Staging Staphylococcaceae Staphylococcus aureus Streptococcus Streptococcus pneumoniae Structure Taxon Testing Time Toddler United States National Institutes of Health Volatile Fatty Acids Work bacterial genetics base deep sequencing genome sequencing microbial community novel pathogen prevent research study small molecule

项目摘要

DESCRIPTION (provided by applicant): This proposal is based on a long-standing and intriguing clinical observation that is directly relevant to human health and concerns the dynamics of human nose and throat microbial communities: about 50% of individuals are not colonized with either Staphylococcus aureus or Streptococcus pneumoniae, and are consequently at low risk for infection by these important pathogens. We hypothesize that these individuals harbor mutualistic antibiotic-producing bacteria in their nose and throat that selectively inhibit the colonization and proliferation of S. aureus and/or S. pneumoniae. Our recent work suggests that in the nostrils, commensal Actinobacteria of the genera Corynebacterium and Propionibacterium inhibit colonization by S. aureus. We have identified strains of these colonization-blocking bacteria that produce small molecules that inhibit S. aureus growth. These beneficial microbes-and the antibiotics they produce-could serve as the basis for novel small molecule and probiotic therapies. An understanding of the role of small-molecule-mediated interactions in the dynamics of nose and throat microbial communities will allow us to develop strategies for preventing and/or eliminating pathogen carriage, drastically decreasing the risk for infection. To test this hypothesis, we take advantage of a unique set of microbiota samples already collected as part of an NIH-funded study of S. pneumoniae carriage. This unique and valuable sample set captures a stage of human development when carriage of S. aureus and S. pneumoniae is in flux; S. pneumoniae carriage rates peak at ~45% in toddlers, a time when S. aureus carriage rates are at a low of ~10%, then S. aureus carriage rates rise as children approach school age reaching ~30% by adolescence. We will use a multi-disciplinary strategy broken down into three aims. In Aim 1, we will use deep sequencing of an extant set of 200 paired nostril and nasopharyngeal microbiota samples to determine which taxa are inversely related with culture-proven S. aureus and S. pneumoniae, and co-culture assays to identify which of these candidate colonization-blocking bacteria produce an antibiotic. In Aim 2, we will use bioassay-guided fractionation to purify these antibiotics from Aim 1 and NMR and MS to solve the their structures. In Aim 3, we will use a combination of bioinformatics and bacterial genetics to identify the genes that encode these antibiotics and we will test whether the presence of antibiotic-encoding genes is negatively correlated with the presence of S. aureus and S. pneumoniae in community metagenomic data from Human Microbiome Project samples. Our efforts will identify new antibiotics that modulate nose and throat microbial community dynamics and impact colonization and infection by two important bacterial pathogens: S. aureus and S. pneumoniae.

描述（由申请人提供）：该提案是基于与人类健康直接相关的长期且有趣的临床观察，并涉及人类鼻子和喉咙微生物群落的动态：大约50％的个体未用金黄色葡萄球菌或链球菌葡萄球菌或肺炎链球菌的葡萄球菌和肺炎链球菌殖民，并且在低风险中受到这些重要的感染风险。我们假设这些个体在其鼻子和喉咙中具有共同产生抗生素的细菌，从而有选择地抑制金黄色葡萄球菌和/或肺炎链球菌的定殖和增殖。我们最近的工作表明，在鼻孔中，菌群属的共生静脉细菌和丙杆菌抑制金黄色葡萄球菌的定殖。我们已经确定了这些定植阻断细菌的菌株，这些细菌产生了抑制金黄色葡萄球菌生长的小分子。这些有益的微生物和它们产生的抗生素是新型小分子和益生菌疗法的基础。了解小分子介导的相互作用在鼻子和喉咙微生物群落动力学中的作用将使我们能够制定防止和/或消除病原体运输的策略，从而大大降低感染风险。为了检验这一假设，我们利用了一组独特的微生物群样品，作为NIH资助的肺炎链球菌托架研究的一部分。当金黄色葡萄球菌和肺炎链球菌的运输中，这种独特而有价值的样品集捕获了人类发展的阶段。幼儿肺炎链球菌的运输速率达到约45％的峰值，这是金黄色葡萄球菌的运输率在低约10％的时候，而S.金黄色葡萄球菌的运输率随着儿童的年龄达到青少年的年龄〜30％。我们将使用分为三个目标的多学科策略。在AIM 1中，我们将对现存的200个配对鼻孔和鼻咽微生物群样品进行深度测序，以确定哪些分类群与培养物 - 预先培养的金黄色葡萄球菌和肺炎链球菌成反比，并共培养分析，以识别哪些候选菌落结肠化结构化细菌产生抗体生产抗体。在AIM 2中，我们将使用生物测定指导的分馏来纯化AIM 1和NMR和MS的这些抗生素来解决它们的结构。在AIM 3中，我们将使用生物信息学和细菌遗传学的组合来识别编码这些抗生素的基因，我们将测试是否测试抗生素编码基因的存在与来自人类微生物组样品的社区宏基因组数据中的金黄色葡萄球菌和肺炎链球菌和肺炎链球菌的存在负相关。我们的努力将确定调节鼻子和喉咙微生物群落动力学的新抗生素，并影响两种重要的细菌病原体的定植和感染：金黄色葡萄球菌和肺炎链球菌。