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）：鲍曼不动杆菌多药耐药（MDR）的出现导致这种革兰氏阴性细菌被指定为传染病的重点。这项工作的长期目标是了解鲍曼不动杆菌耐药性的分子基础和移动遗传元件在耐药性进化中的作用。在鲍曼不动杆菌中，编码抗生素耐药决定因素的基因通常与包括插入序列（IS）在内的可移动遗传元件相关，而在耐多药菌株中，许多耐药基因位于一个横向转移的“耐药岛”（RI）中。来自同一医院的密切相关菌株的基因组测序显示耐药基因补体的差异，这与抗菌药物敏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耐药性演变中的作用将通过对最近三次鲍曼不动杆菌暴发的菌株集合的特征进行前所未有的详细分析来探索。该策略旨在确定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。这些菌株收集将使人们能够在数周至数月的时间内考虑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相关性的广泛模式，并确定随时间的克隆类型在抗性表型上的变化实例。全基因组测序和基因表达分析将提供有关耐药相关基因的存在、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。虽然已知特定基因有助于对某些抗生素产生耐药性，但也可能是药物失活、外排和靶点修饰等多种因素共同作用的结果。对不同菌株的分析将导致鉴定出导致耐药性的替代基因组。这项研究的结果将是更好地了解多药耐药在临床环境中是如何演变的。它还将使我们对鲍曼芽胞杆菌产生抗生素耐药性的机制有一个更完整的认识，这将有助于开发分子诊断分析方法，为选择最合适的治疗方案提供信息。