Function of the Klebsiella pneumoniae RND efflux systems

项目总结/摘要 抗生素的广泛使用推动了抗生素的演变和全球传播， 包括肺炎克雷伯氏菌在内的致病菌中的耐药基因， 对所有临床相关抗生素的耐药性。K.肺炎是院内感染的主要原因 感染，死亡率高，多重耐药，使K。肺炎 除了耐药性外，克雷伯氏菌的高毒力菌株也是一种很难治疗的感染。肺炎， 因为健康个体的社区获得性侵入性感染已经在全球范围内出现。的 K的毁灭性后果。肺炎感染，结合全球传播， K. pneumoniae，导致K.肺炎被识别 被世界卫生组织和疾病控制中心列为紧急健康威胁。 这突出了开发新的治疗方法来治疗 抗微生物药物耐药性感染。在本申请中，我们提供的初步数据显示， 属于抗性-结瘤-感应（RND）超家族的药物外排系统有助于 K.肺炎。除了他们的作用， 抗菌素耐药性，RND外排系统也已被证明是需要多种其他 表型包括毒力所需的表型，但这一过程中涉及的机制 大部分都是未知的。在这个建议中，我们将测试的假设，K。肺炎RND外排 系统对于多种抗生素耐药性和发病机理是必不可少的。我们提出两个目标， 验证我们的假设在目标1中，我们将定义单个K的函数。肺炎RND外排 系统中的抗菌素耐药性，并确定其对体内平衡的影响。在目标2中， 考察了K.肺炎RND转运蛋白与毒力相关 大蜡螟幼虫感染模型中的体外和体内致病潜力的表型。 完成这项工作将确定K的功能。肺炎RND外排系统 抗生素耐药性，生物学和发病机制，并阐明了新的方面K。肺炎 生物学可能导致开发新的治疗方法来治疗抗生素耐药性 K.肺炎感染。

PROJECT SUMMARY/ABSTRACT The widespread use of antibiotics has driven the evolution and global dissemination of resistance genes among pathogenic bacteria including Klebsiella pneumoniae which has evolved resistance to all clinically relevant antibiotics. K. pneumoniae is leading cause of nosocomial infections and has a high mortality rate and multiple drug resistance has made K. pneumoniae infections difficult to treat. In addition to drug resistance, hypervirulent strains of K. pneumoniae that cause community acquired invasive infections in healthy individuals have emerged globally. The devastating consequences of K. pneumoniae infection, combined with the global dissemination of resistance and virulence traits among K. pneumoniae, have led to K. pneumoniae being recognized as an urgent health threat by the World Health Organization and the Centers for Disease Control. This has highlighted the critical need for the development of new therapeutic approaches to treat antimicrobial resistant infections. In this application we present preliminary data showing that multiple drug efflux systems belonging to the Resistance-Nodulation-Sensing (RND) superfamily contribute to the evolution of multiple antibiotic resistance in K. pneumoniae. In addition to their role in antimicrobial resistance, RND efflux systems have also been shown to be required for multiple other phenotypes including phenotypes required for virulence, but the mechanisms involved in this process are largely unknown. In this proposal we will test the hypothesis that the K. pneumoniae RND efflux systems are essential for multiple antibiotic resistance and pathogenesis. We propose two aims to test our hypothesis. In aim 1 we will define the function of the individual K. pneumoniae RND efflux systems in antimicrobial resistance and determine their effect on homeostasis. In aim 2 we will investigate the contribution of the K. pneumoniae RND transporters to virulence-associated phenotypes in vitro and in vivo pathogenic potential in the Galleria mellonella larvae infection model. Completion of this work will define the function of the K. pneumoniae RND efflux systems in antimicrobial resistance, biology and pathogenesis and illuminate novel aspects of K. pneumoniae biology that may lead to the development of novel therapeutic approaches to treat antibiotic resistant K. pneumoniae infections.