Function of the Klebsiella pneumoniae RND efflux systems

项目摘要/摘要 抗生素的广泛使用推动了细菌的进化和全球传播 包括肺炎克雷伯菌在内的病原菌的耐药基因 对所有临床上相关的抗生素都有耐药性。肺炎克雷伯菌是院内感染的主要原因 肺炎克雷伯菌具有较高的死亡率和多重耐药性。 感染很难治疗。除了抗药性外，肺炎克雷伯菌的超强毒力菌株 原因社区获得性侵袭性感染已在全球范围内出现。这个 肺炎克雷伯菌感染的破坏性后果，再加上肺炎克雷伯菌在全球的传播 肺炎克雷伯菌的耐药性和毒力特征导致肺炎克雷伯菌得到认可 被世界卫生组织和疾病控制中心列为紧迫的健康威胁。 这凸显了开发新的治疗方法的迫切需要。 抗菌素耐药性感染。在本申请中，我们提供的初步数据显示了多个 属于抗性-结瘤-传感(RND)超家族的药物外排系统有助于 肺炎克雷伯菌多重耐药性的演变。除了他们在 抗菌素耐药性，RND外排系统也被证明是多种其他 表型包括毒力所需的表型，但这一过程涉及的机制 在很大程度上是未知的。在这项建议中，我们将检验肺炎克雷伯菌RND外排的假设 系统在多重抗生素耐药和发病机制中是必不可少的。我们提出两个目标来 检验我们的假设。在目标1中，我们将定义单个肺炎克雷伯菌RND外排的功能 系统的抗菌素耐药性，并确定其对动态平衡的影响。在《目标2》中我们将 探讨肺炎克雷伯菌RND转运体对毒力相关的作用 梅隆沙门氏菌幼虫感染模型的体外表型和体内致病潜能。 这项工作的完成将确定肺炎克雷伯菌RND外排系统在 肺炎克雷伯菌的耐药性、生物学及致病机制 可能导致开发治疗抗生素耐药性的新治疗方法的生物学 肺炎克雷伯菌感染。

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.