Identification of antimicrobial specialized metabolites from the human oral microbiome to target multidrug-resistant pathogens

从人类口腔微生物组中鉴定抗菌专门代谢物以靶向多重耐药病原体

• 批准号: 10605700
• 负责人: SUSAN ZELASKO
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605700
• 关键词: Aerodigestive Tract; Age; Animals; Antibiotic Resistance; Antibiotics; Autoimmune Diseases; Bacteria; Caliber; Cardiovascular Diseases; Clinical; Clinical Skills; Communication; Dangerousness; Disease; Environment; Evaluation Studies; Fractionation; Gatekeeping; Gene Cluster; Genome; Genomics; Genus staphylococcus; Growth; Health; Human; Human Microbiome; Infection; Integration Host Factors; Invaded; Laboratories; Lead; Life; Lower Gastrointestinal Tract; Mediating; Medical; Mentorship; Metadata; Metagenomics; Microbe; Microbiology; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Natural Products; Nose; Oral; Oral cavity; Participant; Pathogenicity; Peptides; Periodicity; Pharmaceutical Preparations; Physicians; Play; Population Heterogeneity; Predisposition; Prevention; Prevotella; Procedures; Production; Research; Research Training; Resources; Respiratory System; Ribosomes; Risk Factors; Role; Salivary; Sampling; Scientist; Shapes; Shotguns; Site; Source; Streptococcus; Structure; Swab; Testing; Therapeutic immunosuppression; United States; Universities; Vancomycin resistant enterococcus; War; Wisconsin; Work; antibiotic resistant infections; antimicrobial; antimicrobial drug; bactericide; career; colonization resistance; comparative; drug development; drug resistant microorganism; drug resistant pathogen; dysbiosis; efficacy testing; fecal microbiome; health determinants; human microbiota; immunoregulation; in vivo; insight; metabolomics; metagenome; metagenomic sequencing; microbial community; microbiome; microbiota; microorganism; multi-drug resistant pathogen; oral microbial community; oral microbiome; oral streptococci; pathogen; polyketides; prevent; reference genome; safety testing; screening; small molecule; socioenvironmental factor; urban setting

PROJECT SUMMARY / ABSTRACT Our microbiome plays a key role in colonization resistance, which is the prevention of growth, persistence, and subsequent infection by pathogenic microorganisms. Disruptions in an established microbial community and its functioning can alter infection susceptibility. Understanding how changes in the oral microbiome render it vulnerable to pathogen colonization is essential, as carriage of drug-resistant microbes is a major risk factor for developing serious and difficult-to-treat infections. One mechanism by which our microbiome acts to prevent pathogen colonization is through the production of antimicrobial specialized metabolites (ASMs) that directly inhibit the growth of competing microbes. Identification of such bioactive metabolites can be facilitated by examining the biosynthetic gene clusters (BGC) that encode them. Analysis of reference genomes generated through the Human Microbiome Project identified 3,118 BGCs across various body sites, with the typical oral cavity containing high BGC abundance (1,061+/-143 clusters). The microbiota inhabiting this site represent a first point of contact with the environment and invading microbes, and therefore, play a vital gatekeeping role against pathogen dissemination to the lower gastrointestinal and respiratory tracts. Yet, the structure and function of ASMs produced by human-associated microbiota remains limited, particularly within the oral cavity. This proposal seeks to leverage a combination of comparative metagenomic and metabolomic approaches to determine the role of ASM production by oral-associated bacteria in defense against multidrug-resistant organisms (MDRO). The specific aims are to 1) define differences in oral microbiomes between MDRO carriers versus non-carriers and assess how determinants of health associate with abundance of key taxa, and 2) evaluate the production of bioactive ASMs by oral-associated bacteria from MDRO carriers versus non-carriers. These objectives will be accomplished through shotgun metagenomic sequencing of oral microbiome samples from diverse populations, paired with analysis of detailed associated metadata relating to health and MDRO carriage risk factors. Identification of antimicrobial metabolite producing bacteria will be achieved through high-throughput bioactivity-guided fractionation, followed by metabolomic analysis and in vivo efficacy testing. The study of ASM production by oral microbiota will yield insight into the factors shaping this dynamic microbial community and serve as an untapped source for much-needed, new antimicrobial drug leads. The unmatched caliber of microbiology research performed at the University of Wisconsin-Madison will provide an ideal environment to carry out the proposed work. Resources and mentorship provided by project sponsor Dr. Cameron Currie and collaborators will facilitate the timely completion of this proposal. Moreover, execution of this tailored research training plan will enable the applicant to develop the necessary experimental, communication, and clinical skills for a successful transition to a career as a physician-scientist.

项目摘要 /摘要 我们的微生物组在定殖抗性中起关键作用，这是预防生长，持久性和 随后通过致病性微生物感染。在一个已建立的微生物社区及其它的破坏 功能可以改变感染的敏感性。了解口腔微生物组的变化如何呈现 容易受到病原体定殖的影响是必不可少的，因为耐药微生物的运输是主要的风险因素 发展严重且难以治疗的感染。我们的微生物组可防止的一种机制 病原体定植是通过直接的抗菌专用代谢产物（ASM）的生产 抑制竞争微生物的增长。可以促进这种生物活性代谢物的识别 检查编码它们的生物合成基因簇（BGC）。产生的参考基因组分析 通过人类微生物组项目，在各个身体部位确定了3,118 bgc，典型的口服 含有高BGC丰度的腔（1,061 +/- 143个簇）。居住在该站点的微生物群代表 与环境和入侵微生物接触的第一点，因此起着至关重要的守门作用 反对病原体向胃肠道和呼吸道下部传播。但是，结构和 由人类相关的微生物群产生的ASM的功能仍然有限，尤其是在口腔内。 该建议旨在利用比较元基因组和代谢组方法的结合 确定口腔相关细菌在防御抗多药中产生ASM的作用 生物（MDRO）。具体目的是1）定义MDRO之间口服微生物的差异 携带者与非携带者，并评估健康的决定因素如何与大量关键联系在一起 分类单元和2）评估通过MDRO载体与口腔相关细菌的生物活性ASM的产生 相对于非载体。这些目标将通过口服的shot弹枪宏基因组测序来实现 来自不同种群的微生物组样本，与与详细相关元数据的分析相关 健康和MDRO运输风险因素。鉴定抗菌代谢物产生细菌将是 通过高通量生物活性引导的分馏，然后进行代谢组分析和体内 功效测试。口服微生物群对ASM生产的研究将洞悉塑造这一点的因素 动态微生物群落，并作为急需的新抗菌药物铅的未开发的来源。 威斯康星大学麦迪逊分校进行的无与伦比的微生物研究能力将提供 进行拟议的工作的理想环境。项目赞助商提供的资源和指导 卡梅隆·柯里（Cameron Currie）博士和合作者将促进该提案的及时完成。此外，执行 该量身定制的研究培训计划将使申请人能够开发必要的实验性， 沟通和临床技能成功过渡到医生科学家职业。