Function of the Klebsiella pneumoniae RND efflux systems

肺炎克雷伯菌 RND 外排系统的功能

基本信息

批准号：
10649576
负责人：
JAMES Edward BINA
金额：
$ 23.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649576
关键词：
Acids Address Affect Antibiotic Resistance Antibiotics Antimicrobial Resistance Bacteria Bile fluid Biology Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Chimeric Proteins Classification Communities Data Development Disease Drug Efflux Drug resistance Environment Escherichia coli Evolution Feedback Gene Expression Gene Proteins Genes Genetic Transcription Gram-Negative Bacteria Grant Growth Health Homeostasis Impairment In Vitro Individual Infection Iron Klebsiella pneumoniae Laboratories Larva Link Mediating Membrane Membrane Fusion Metabolism Microbial Biofilms Modeling Multi-Drug Resistance Nosocomial Infections Pathogenesis Pathogenicity Patients Pattern Persons Phase Phenotype Phosphotransferases Play Pneumonia Pore Proteins Process Production Proteins Protons Pump Repression Research Resistance Role Structure System Testing Therapeutic Transcription Initiation VDAC1 gene Vibrio cholerae Virulence Virulent Work World Health Organization antimicrobial antimicrobial resistant infection antiporter biological adaptation to stress capsule cell growth clinically relevant design efflux pump environmental adaptation follow-up global health healthcare-associated infections human pathogen in vivo mortality mutant novel novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria periplasm resistance gene resistant Klebsiella pneumoniae response sensor trait transcriptome virulence gene

项目摘要

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.

项目概要/摘要抗生素的广泛使用推动了抗生素的进化和全球传播包括肺炎克雷伯菌在内的病原菌中的耐药基因已进化对所有临床相关抗生素产生耐药性。肺炎克雷伯菌是院内感染的主要原因肺炎克雷伯菌感染率高、死亡率高、多重耐药性感染难以治疗。除了耐药性之外，肺炎克雷伯菌的高毒力菌株还导致健康个体的社区获得性侵袭性感染在全球范围内出现。这肺炎克雷伯菌感染的毁灭性后果，加上全球传播肺炎克雷伯菌的耐药性和毒力特征，导致肺炎克雷伯菌被认识世界卫生组织和疾病控制中心将其列为紧急健康威胁。这突出表明迫切需要开发新的治疗方法来治疗抗菌药物耐药性感染。在此应用中，我们提供了初步数据，表明多个属于耐药-结节-传感（RND）超家族的药物流出系统有助于肺炎克雷伯菌多重抗生素耐药性的演变。除了他们的角色抗微生物药物耐药性，RND 外排系统也已被证明是多种其他表型包括毒力所需的表型，但该过程涉及的机制很大程度上是未知的。在本提案中，我们将检验肺炎克雷伯菌 RND 流出的假设系统对于多种抗生素耐药性和发病机制至关重要。我们提出两个目标检验我们的假设。在目标 1 中，我们将定义个体肺炎克雷伯氏菌 RND 流出的功能抗菌素耐药性系统并确定其对体内平衡的影响。在目标 2 中，我们将研究肺炎克雷伯菌 RND 转运蛋白对毒力相关的贡献大蜡螟幼虫感染模型中体外和体内致病潜力的表型。这项工作的完成将定义肺炎克雷伯氏菌 RND 外排系统的功能抗菌素耐药性、生物学和发病机制，并阐明肺炎克雷伯菌的新方面生物学可能会导致开发治疗抗生素耐药性的新治疗方法肺炎克雷伯菌感染。