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 我们的微生物群在抵抗定居方面起着关键作用，这是防止生长、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 功能可以改变感染的易感性。了解口腔微生物群的变化是如何导致它的 易受病原体定植是必不可少的，因为携带耐药微生物是 出现严重和难以治疗的感染。我们的微生物群通过一种机制来防止 病原体定植是通过产生抗微生物的专门代谢物(ASM)直接 抑制相互竞争的微生物的生长。这样的生物活性代谢物的鉴定可以通过 检查编码它们的生物合成基因簇(BGC)。产生的参考基因组的分析 通过人类微生物组计划，在不同的身体部位发现了3118个BGC，典型的口腔 包含高BGC丰度(1,061+/-143团)的空腔。栖息在该地点的微生物区系代表着 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 防止病原体扩散到下消化道和呼吸道。然而，它的结构和 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。 这项建议寻求利用比较元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在防御多重耐药中的作用 有机体(MDRO)。具体目的是：1)确定MDRO和MDRO在口腔微生物区系上的差异 携带者与非携带者，并评估健康决定因素如何与大量关键因素相关联 2)评估MDRO携带者口腔相关细菌产生生物活性ASM的情况 与非携带者相比。这些目标将通过口腔的元基因组测序来实现 来自不同人群的微生物组样本，以及与以下相关的详细相关元数据的分析 健康和MDRO运输风险因素。将对产生抗微生物代谢产物的细菌进行鉴定 通过高通量生物活性引导分级，然后进行代谢组学分析和体内 药效测试。对口腔微生物群产生ASM的研究将有助于深入了解影响这一现象的因素 具有活力的微生物群落，并作为急需的新抗菌药物线索的未开发来源。 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 卡梅隆·柯里博士和合作者将为及时完成这项提案提供便利。此外，执行 这一量身定制的研究培训计划将使申请者能够开发必要的实验， 沟通，以及成功过渡到医生-科学家职业生涯的临床技能。