Evolution of multidrug resistance in Acinetobacter baumannii

鲍曼不动杆菌多重耐药性的演变

• 批准号: 8107146
• 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/8107146
• 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. PUBLIC HEALTH RELEVANCE: Public health relevance. Bacteria can evolve rapidly to evade killing by antibiotics. This project will determine the genetic changes that happen over short time periods leading to antibiotic resistance. These changes include exchange of resistance genes among isolates and activation of genes by mobile genetic elements. Knowledge of the mechanisms and frequency of genetic change will help in the design of strategies to detect antimicrobial resistance and select the best therapy for treatment of infections.

描述（由申请方提供）：鲍曼不动杆菌中出现多药耐药性（MDR），导致该革兰氏阴性菌被指定为感染性疾病的优先治疗菌。这项工作的长期目标是了解A.以及移动的遗传元件在抗性进化中的作用。编码抗生素抗性决定簇移动的基因经常与A.包括插入序列（IS）的鲍曼不动杆菌，并且在MDR菌株中，许多抗性基因共同位于横向转移的“抗性岛”（RI）中。来自同一家医院的密切相关菌株的基因组测序揭示了与抗菌药物敏感性模式差异相对应的耐药基因互补的变化。移动的遗传元件和其他遗传变化在抗生素耐药性进化中的作用将通过对最近三个A.鲍曼不动杆菌爆发的细节前所未有该策略旨在识别广泛耐药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。这些菌株收集将使人们能够考虑与抗生素耐药性变化相关的数周至数月的遗传变化。将使用分子测序分型来建立菌株间相关性的广泛模式，并通过克隆类型鉴定耐药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与抗性相关的基因的存在、组织和调控的详细信息。通过系统发育分析确定IS元件的动员速率和RI的变化。尽管已知特定基因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组合的结果。对不同菌株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了解多药耐药性如何在临床环境中演变。这也将导致更完整的看法，导致抗生素耐药性的机制，在A。鲍曼不动杆菌，这将有助于发展分子诊断分析，以选择最合适的治疗方案。 公共卫生相关性：公共卫生相关性。细菌可以迅速进化以逃避抗生素的杀伤。该项目将确定在短时间内发生的导致抗生素耐药性的遗传变化。这些变化包括菌株间抗性基因的交换和移动的遗传因子对基因的激活。了解遗传变化的机制和频率将有助于设计检测抗菌素耐药性的策略，并选择治疗感染的最佳疗法。