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）：该提案基于一项长期且有趣的临床观察，该观察与人类健康直接相关，并涉及人类鼻子和喉咙微生物群落的动态：约 50% 的个体没有被葡萄球菌定植金黄色葡萄球菌或肺炎链球菌，因此被这些重要病原体感染的风险较低。我们假设这些人的鼻子和喉咙里含有互利的抗生素产生细菌，可以选择性地抑制金黄色葡萄球菌和/或肺炎链球菌的定植和增殖。我们最近的研究表明，在鼻孔中，棒状杆菌属和丙酸杆菌属的共生放线菌抑制金黄色葡萄球菌的定植。我们已经鉴定出这些定植阻断细菌的菌株，它们产生抑制金黄色葡萄球菌生长的小分子。这些有益的微生物及其产生的抗生素可以作为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态中的作用将使我们能够制定预防和/或消除病原体携带的策略，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样本，这些样本是 NIH 资助的肺炎链球菌携带研究的一部分。这个独特且有价值的样本集捕捉到了金黄色葡萄球菌和肺炎链球菌携带不断变化的人类发育阶段；在幼儿中，肺炎链球菌携带率最高可达约 45%，此时金黄色葡萄球菌携带率低至约 10%，然后随着儿童接近学龄，金黄色葡萄球菌携带率上升，到青春期时达到约 30%。我们将采用多学科策略，分为三个目标。在目标 1 中，我们将使用对现有 200 个配对鼻孔和鼻咽微生物群样本的深度测序来确定哪些分类群与经培养证明的金黄色葡萄球菌和肺炎链球菌呈负相关，并通过共培养测定来识别其中哪些分类群候选定植阻断细菌会产生抗生素。在目标 2 中，我们将使用生物测定引导的分馏从目标 1 中纯化这些抗生素，并使用 NMR 和 MS 来解析其结构。在目标 3 中，我们将结合生物信息学和细菌遗传学来识别编码这些抗生素的基因，并测试是否人类微生物组计划样本的群落宏基因组数据中，抗生素编码基因的存在与金黄色葡萄球菌和肺炎链球菌的存在呈负相关。我们的努力将找到新的抗生素，这些抗生素可以调节鼻子和喉咙微生物群落的动态，并影响两种重要细菌病原体的定植和感染：金黄色葡萄球菌和肺炎链球菌。