Evolution of multidrug resistance in Acinetobacter baumannii

鲍曼不动杆菌多重耐药性的演变

基本信息

批准号：
8535790
负责人：
Mark D ADAMS
金额：
$ 31.01万
依托单位：
J. CRAIG VENTER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535790
关键词：
Academic Medical Centers Acinetobacter baumannii Antibiotic Resistance Antibiotics Antimicrobial Resistance Antimicrobial susceptibility Bacteria Biological Assay Clinical Collection Communicable Diseases Complement DNA Insertion Elements Data Development Diagnostic Disease Outbreaks Elements Environment Evolution Extreme drug resistant tuberculosis Family Frequencies Gene Activation Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Genotype Goals Gram-Negative Bacteria Health care facility Health system Hospitals IS Elements Immunocompromised Host Infection Island Knowledge Lead Left Length of Stay Maryland Medical center Mobile Genetic Elements Modification Molecular Molecular Profiling Morbidity - disease rate Multi-Drug Resistance Mutation Nature Other Genetics Outcome Study Patients Pattern Pharmaceutical Preparations Phenotype Phylogenetic Analysis Population RNA Sequences Regimen Resistance Role Sampling Sampling Studies Series Site Sputum Staining method Stains Structure Therapeutic Time United States University Hospitals Variant Work base combat comparative design genome sequencing genome-wide improved insight killings mortality public health relevance resistant strain tool

Academic Medical Centers Acinetobacter baumannii Antibiotic Resistance Antibiotics Antimicrobial Resistance Antimicrobial susceptibility Bacteria Biological Assay Clinical Collection Communicable Diseases Complement DNA Insertion Elements Data Development Diagnostic Disease Outbreaks Elements Environment Evolution Extreme drug resistant tuberculosis Family Frequencies Gene Activation Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Genotype Goals Gram-Negative Bacteria Health care facility Health system Hospitals IS Elements Immunocompromised Host Infection Island Knowledge Lead Left Length of Stay Maryland Medical center Mobile Genetic Elements Modification Molecular Molecular Profiling Morbidity - disease rate Multi-Drug Resistance Mutation Nature Other Genetics Outcome Study Patients Pattern Pharmaceutical Preparations Phenotype Phylogenetic Analysis Population RNA Sequences Regimen Resistance Role Sampling Sampling Studies Series Site Sputum Staining method Stains Structure Therapeutic Time United States University Hospitals Variant Work base combat comparative design genome sequencing genome-wide improved insight killings mortality public health relevance resistant strain tool

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项目摘要

DESCRIPTION (provided by applicant): The emergence of multidrug resistance (MDR) in Acinetobacter baumannii has resulted in the designation of this Gram negative bacterium as a priority in Infectious Diseases. The long-term goal of this work is to understand the molecular basis for antibiotic resistance in A. baumannii and the role of mobile genetic elements in the evolution of resistance. Genes encoding antibiotic resistance determinants are frequently associated with mobile genetic elements in A. baumannii including insertions sequences (IS) and in MDR strains many resistance genes are co-located in a laterally transferred 'resistance island' (RI). Genome sequencing of closely related strains from the same hospital revealed variation in the complement of resistance genes that corresponded with differences in antimicrobial susceptibility pattern. The role of mobile genetic elements and other genetic changes in the evolution of antibiotic resistance will be explored through characterization of collections of strains from three recent A. baumannii outbreaks in unprecedented detail. The strategy is designed to identify genotypic variation among extensively drug resistant strains and phenotypic variation among genotypically similar or identical strains. These strain collections will enable consideration of genetic changes over time periods of weeks to months that are associated with changes in antibiotic resistance. Molecular sequencing typing will be used to establish broad patterns of relatedness among strains and to identify instances of variation in resistance phenotype over time by clone type. Whole-genome sequencing and gene expression analysis will provide detailed information about the presence, organization, and regulation of genes associated with resistance. The rate of mobilization of IS elements and changes in the RI will be determined through phylogenetic analysis. Although specific genes are known to contribute to resistance to certain antibiotics, it is also likely that high level resistance is the result of a combination of factors including drug inactivation, efflux, and target site modification. Analysis of diverse stains will lead to identification of alternative gene sets that lead to resistance. The outcome of this study will be a better understanding of how multidrug resistance evolves in a clinical setting. It will also result in a more complete view of the mechanisms that lead to antibiotic resistance in A. baumannii, which will assist in development of molecular diagnostic assays to inform selection of the most appropriate therapeutic regimen.

描述（由申请人提供）：鲍曼尼氏杆菌中多药耐药性（MDR）的出现导致该革兰氏阴性细菌称为感染性疾病的优先事项。这项工作的长期目标是了解鲍曼尼抗抗生素耐药性的分子基础，以及移动遗传元素在抗性进化中的作用。编码抗生素耐药性决定因素的基因经常与鲍曼尼曲霉中的移动遗传元素有关，包括插入序列（IS）和MDR菌株中许多抗性基因在横向转移的“电阻岛”（RI）中共分配。来自同一医院密切相关菌株的基因组测序表明，抗药性基因的补体差异与抗菌易感性模式的差异相对应。移动遗传元件和其他遗传变化在抗生素抗性演化中的作用将通过表征从前所未有的细节来表征来自最近三个鲍曼尼爆疫苗爆发的三种疫苗的菌株的集合来探索。该策略旨在识别基因型抗药性菌株之间的基因型变异和基因型相似或相同菌株之间的表型变异。这些应变收集将使您可以考虑与抗生素耐药性变化相关的数周到数月的遗传变化。分子测序分型将用于建立菌株之间的广泛相关性模式，并通过克隆类型确定抗性表型变化的实例。全基因组测序和基因表达分析将提供有关与抗性相关的基因的存在，组织和调节的详细信息。 IS元素的动员速率，RI的变化将通过系统发育分析确定。尽管已知特定的基因有助于对某些抗生素的抗性，但高水平的耐药性也可能是包括药物失活，外排和靶位部位修饰在内的因素组合的结果。对各种污渍的分析将导致鉴定导致抗性的替代基因集。这项研究的结果将更好地理解多药在临床环境中如何发展。这也将导致对鲍曼尼曲霉的抗生素耐药性的机制进行更完整的视野，这将有助于开发分子诊断测定法，以告知选择最合适的治疗方案。