Function of the Klebsiella pneumoniae RND efflux systems

肺炎克雷伯菌 RND 外排系统的功能

• 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
• 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

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.

项目摘要/摘要 抗生素的广泛使用推动了对全球的发展和全球传播 病原细菌中的抗性基因，包括肺炎克雷伯氏菌的耐药性基因 对所有临床相关抗生素的抗性。 K.肺炎是医院的主要原因 感染且死亡率高，多种耐药性使肺炎。 感染难以治疗。除耐药性外，肺炎的高毒性菌株 由于社区获得了健康个体的侵入性感染，因此在全球范围内出现。这 K.肺炎感染的毁灭性后果，加上全球传播 肺炎链球菌的耐药性和毒力性状已导致肺炎被识别 作为世界卫生组织和疾病控制中心的紧急健康威胁。 这强调了开发新的治疗方法的关键需求 抗菌抗性感染。在此应用程序中，我们提供初步数据，显示多个 属于抗药性 - 结节感应（RND）超家族的药物外排系统有助于 多种抗生素耐药性在肺炎链球菌中的演变。除了他们在 抗菌素抗性，RND外排系统也被证明是多个其他的 表型包括毒力所需的表型，但是此过程中涉及的机制 在很大程度上未知。在此提案中，我们将检验以下假设。 系统对于多种抗生素耐药性和发病机理至关重要。我们提出了两个目标 检验我们的假设。在AIM 1中，我们将定义单个K.肺炎的功能 抗菌素耐药性的系统，并确定其对稳态的影响。在目标2中，我们将 研究肺炎链球菌RND转运蛋白对毒力相关的贡献 在梅洛尼亚氏菌感染模型中，体外和体内致病潜力的表型。 这项工作的完成将定义K.肺炎RND外排系统的功能 抗菌素耐药性，生物学和发病机理，并阐明了肺炎的新颖方面 可能导致新型治疗方法来治疗抗生素耐药性的生物学 K.肺炎感染。