Characterizing novel Beta-lactamases from metagenomic samples: insights into the evolution of antimicrobial resistance from the environment towards human-associated pathogens

从宏基因组样本中表征新型 β-内酰胺酶：深入了解从环境到人类相关病原体的抗菌药物耐药性的演变

• 批准号: 10450287
• 负责人: Pablo Power
• 金额: $ 12.77万
• 依托单位: UBATEC S.A.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450287
• 关键词: Alaska; Alaskan; Antarctica; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Attention; Bacteria; Biochemical; Biological Assay; Carbapenems; Classification; Clinic; Clinical; Cloning; Collection; Crystallization; Early Diagnosis; Environment; Enzymes; Evolution; Exhibits; Exposure to; Frequencies; Fright; Genes; Genetic; Health; Hospitals; Human; Kinetics; Lactamase; Mediating; Metagenomics; Methods; Microbiology; Mission; Molecular; Monobactams; Mutagenesis; Mutation; Names; National Institute of Allergy and Infectious Disease; Nature; Phenotype; Physicians; Plague; Process; Production; Proteins; Public Health; Research; Resistance; Risk; Role; Route; Sampling; Site-Directed Mutagenesis; Soil; Source; Spectrophotometry; Structure; System; Techniques; United States National Institutes of Health; Variant; X ray diffraction analysis; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; enzyme pathway; insight; member; metagenome; microorganism; novel; pathogen; pathogenic bacteria; recruit; remote location; repository; resistance mechanism; screening; soil sampling; trend

PROJECT SUMMARY β-Lactamases are the most widespread resistance mechanism to β-lactam antibiotics. Of particular concern are a group of β-lactamases known as carbapenemases, named for their ability to destroy our newest β-lactam antibiotics, the carbapenems. The rise of carbapenem resistance is a recent global trend that has resulted in pan-national fear. An interesting approach to understand carbapenem resistance and how it evolves is through quantitative analysis of non-pathogenic microorganisms found in the environment. Analysis of these microorganisms offers the intriguing possibility of predicting how antibiotic resistance may evolve and provides clinicians with an “early warning” system for the advent of novel resistance mechanisms in pathogenic bacteria. Previous research has shown that the soil is an excellent repository for many β-lactamases, especially carbapenemases. The main part of the project will be the study of a collection of metagenome-origin β-lactamases isolated from Alaskan soil, named LRA (for “β-lactam resistance from Alaska”). This metagenomic approach will be expanded and applied to the analysis of soil samples from Antarctica to identify β-lactamase-mediated resistance in different isolated regions. Identified environmental β-lactamases will be characterized using a multi-pronged approach involving phenotypic, molecular, biochemical and structural techniques. Specifically, results from this comprehensive analysis will allow us to assess the evolutionary routes of β-lactamases found among clinical pathogens that plague human health today, and to evaluate novel niches of potentially unexplored genes that could be recruited by these pathogens.

项目概要 β-内酰胺酶是最广泛的β-内酰胺抗生素耐药机制。 令人担忧的是一组被称为碳青霉烯酶的 β-内酰胺酶，因其破坏细菌的能力而得名。 我们最新的 β-内酰胺抗生素，碳青霉烯类抗生素 碳青霉烯类抗生素耐药性的兴起是最近才出现的。 全球趋势导致了全国性的恐惧。这是一种有趣的理解方法。 碳青霉烯类耐药性及其演变是通过对非致病性的定量分析 对环境中发现的微生物的分析提供了有趣的结果。 预测抗生素耐药性如何演变的可能性，并为信徒提供了 病原菌新耐药机制出现的“预警”系统。 先前的研究表明，土壤是许多 β-内酰胺酶的极好储存库， 该项目的主要部分将是对一系列碳青霉烯酶的研究。 从阿拉斯加土壤中分离出的宏基因组起源 β-内酰胺酶，命名为 LRA（“β-内酰胺抗性”） 来自阿拉斯加”）。这种宏基因组方法将被扩展并应用于土壤分析。 来自南极洲的样本，以确定不同隔离区域中 β-内酰胺酶介导的耐药性。 将使用多管齐下的方法来表征已识别的环境β-内酰胺酶 具体来说，结果来自 这种综合分析将使我们能够评估所发现的 β-内酰胺酶的进化路线 当今困扰人类健康的临床病原体，并评估新的生态位 这些病原体可能会招募潜在的未开发基因。