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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.

项目总结/文摘