Evolution of multidrug resistance in Acinetobacter baumannii

鲍曼不动杆菌多重耐药性的演变

• 批准号: 8325561
• 负责人: Mark D ADAMS
• 金额: $ 32.14万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 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/8325561
• 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 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

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）：鲍曼不动杆菌中多药耐药性（MDR）的出现导致这种革兰氏阴性细菌被指定为传染病的优先细菌。这项工作的长期目标是了解鲍曼不动杆菌抗生素耐药性的分子基础以及移动遗传元件在耐药性进化中的作用。编码抗生素抗性决定簇的基因经常与鲍曼不动杆菌中的可移动遗传元件相关，包括插入序列（IS），并且在MDR菌株中，许多抗性基因共位于横向转移的“抗性岛”（RI）中。来自同一医院的密切相关菌株的基因组测序揭示了耐药基因互补的变化，这与抗菌药物敏感性模式的差异相对应。通过对最近三起鲍曼不动杆菌爆发的菌株集合进行前所未有的详细表征，我们将探索移动遗传元件和其他遗传变化在抗生素耐药性进化中的作用。该策略旨在识别广泛耐药菌株之间的基因型变异以及基因型相似或相同菌株之间的表型变异。这些菌株收集将能够考虑数周至数月期间与抗生素耐药性变化相关的遗传变化。分子测序分型将用于建立菌株之间的广泛相关性模式，并根据克隆类型识别抗性表型随时间变化的情况。全基因组测序和基因表达分析将提供有关与耐药性相关的基因的存在、组织和调控的详细信息。 IS 元素的动员率和 RI 的变化将通过系统发育分析来确定。尽管已知特定基因会导致对某些抗生素的耐药性，但高水平耐药性也可能是药物失活、外排和靶位点修饰等因素综合作用的结果。对不同染色剂的分析将导致鉴定导致抗性的替代基因组。这项研究的结果将是更好地了解临床环境中多重耐药性如何演变。它还将使我们对导致鲍曼不动杆菌抗生素耐药性的机制有更全面的了解，这将有助于分子诊断分析的发展，以帮助选择最合适的治疗方案。