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.

项目概要/摘要 我们的微生物组在定植抵抗中发挥着关键作用，即防止生长、持久性和 随后被病原微生物感染。已建立的微生物群落的破坏及其 功能可以改变感染易感性。了解口腔微生物组的变化如何导致它 容易受到病原体定植的影响至关重要，因为携带耐药微生物是导致感染的主要危险因素 发生严重且难以治疗的感染。我们的微生物组预防的一种机制 病原体定植是通过产生抗菌专门代谢物 (ASM) 来直接 抑制竞争性微生物的生长。可以通过以下方式促进此类生物活性代谢物的鉴定 检查编码它们的生物合成基因簇（BGC）。分析生成的参考基因组 通过人类微生物组项目，在不同的身体部位发现了 3,118 个 BGC，其中典型的口腔微生物组 空腔含有高 BGC 丰度（1,061+/-143 簇）。居住在该地点的微生物群代表了 与环境和入侵微生物的第一个接触点，因此发挥着至关重要的把关作用 防止病原体传播到下消化道和呼吸道。然而，结构和 由人类相关微生物群产生的 ASM 的功能仍然有限，特别是在口腔内。 该提案旨在利用比较宏基因组学和代谢组学方法的组合来 确定口腔相关细菌产生 ASM 在防御多重耐药性中的作用 有机体（多重耐药菌）。具体目标是 1) 定义 MDRO 之间口腔微生物组的差异 携带者与非携带者的比较，并评估健康的决定因素如何与关键的丰度相关 分类单元，2) 评估来自 MDRO 携带者的口腔相关细菌产生的生物活性 ASM 与非运营商相比。这些目标将通过口腔的鸟枪法宏基因组测序来实现 来自不同人群的微生物组样本，并结合对相关详细相关元数据的分析 健康和 MDRO 携带风险因素。产生抗菌代谢物的细菌的鉴定将 通过高通量生物活性引导的分级分离、随后进行代谢组学分析和体内 功效测试。通过口腔微生物群生产 ASM 的研究将有助于深入了解影响这一现象的因素 动态微生物群落，并作为急需的新抗菌药物先导物的未开发来源。 威斯康星大学麦迪逊分校进行的无与伦比的微生物学研究将提供 开展拟议工作的理想环境。项目发起人提供的资源和指导 Cameron Currie 博士和合作者将促进该提案的及时完成。此外，执行 这个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， 沟通和临床技能，以成功过渡到医师科学家的职业生涯。