Evolution of multidrug resistance in Acinetobacter baumannii

描述(由申请人提供)：鲍曼不动杆菌多重耐药(MDR)的出现导致这种革兰氏阴性菌被指定为传染病的优先考虑因素。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，以及可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经常与可移动的遗传元件相关，包括插入序列(IS)，而在MDR株中，许多耐药基因共位于一个横向转移的耐药岛(RI)上。来自同一家医院的密切相关菌株的基因组测序显示，耐药基因的补体存在差异，这与药物敏感性模式的差异相对应。将通过对最近三次鲍曼不动杆菌暴发的菌株集合进行前所未有的详细描述，来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变异，以及基因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几周到几个月的时间段内与抗生素耐药性变化相关的基因变化。分子测序分型将用于建立菌株之间广泛的相关性模式，并根据克隆类型确定耐药表型随时间的变化情况。全基因组测序和基因表达分析将提供与抗性相关基因的存在、组织和调控的详细信息。IS分子的动员速度和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灭活、外排和靶点修饰等因素综合作用的结果。对不同菌株的分析将导致识别导致耐药性的替代基因集。这项研究的结果将是更好地理解多药耐药性在临床环境中是如何演变的。它还将导致对鲍曼不动杆菌耐药机制的更全面的了解，这将有助于开发分子诊断分析，为选择最合适的治疗方案提供信息。

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.