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Investigating a Novel Co-regulation of Multi-Drug Efflux Pumps and Polysaccharide Capsule in E. coli

研究大肠杆菌中多药物外排泵和多糖胶囊的新型协同调节

基本信息

批准号：
9242912
负责人：
Mehreen Arshad
金额：
$ 18.85万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-18 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242912
关键词：
Address Ambulatory Care Animal Model Anti-Infective Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Award Bacteria Binding Binding Sites Biogenesis Bladder Centers for Disease Control and Prevention (U.S.)Childhood Communicable Diseases Complement DNA Deuterium Disease Down-Regulation Drug Efflux Effectiveness Escherichia coli Faculty Foundations Funding Gene Expression Genes Genetic Transcription Genomics Goals Green Fluorescent Proteins Hydrogen Immune system Infection K-Series Research Career Programs Knock-out Knowledge Laboratories Ligand Binding Ligands Mass Spectrum Analysis Measurement Medical Mentorship Modeling Molecular Molecular Conformation Morbidity - disease rate Multi-Drug Resistance Mus Mutagenesis Organism Outpatients Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Polysaccharides Positioning Attribute Predisposition Promoter Regions Proteins Public Health Regulation Regulatory Pathway Research Research Institute Research Personnel Research Proposals Role Seeds Sepsis Site Specimen Support System Testing Training Transcription Repressor/Corepressor Universities Up-Regulation Urinary tract infection Uropathogenic E. coli Virulence Virulence Factors Visit Work Xenobiotics antimicrobial attenuation bacterial genetics capsule career chemical genetics chromatin immunoprecipitation community-acquired UTI cost efflux pump experimental study genetic approach genome-wide immune clearance inhibitor/antagonist innovation interest microbial mortality mouse model mutant novel novel therapeutics pathogen programs protein structure public health emergency receptor response skills small molecule small molecule inhibitor transcriptome

项目摘要

PROJECT SUMMARY In this application, I am requesting a career development award to support my research proposal titled “Investigating a Novel Co-regulation of Multi-Drug Efflux Pumps and Polysaccharide Capsule in E. coli.” I will be undertaking this work under the mentorship of Dr. Patrick Seed at Duke University. The aims of this proposal arose out of my interest in identifying virulence specific factors that can be used as targets for new classes of antimicrobials against Gram negative organisms. Uropathogenic E. coli (UPEC) is one of the most common Gram negative and a major cause of urinary tract infection (UTI). However, rapidly rising antibiotic resistance threatens the effectiveness of all commonly used antibiotics. In addition the global rise of the multi- drug resistant (MDR) UPEC clonal subtype ST131 has been termed an urgent threat to public health by the Centers for Disease Control. Together this underscores the critical need to identify new antimicrobial strategies. Since most cases of community acquired UTI occur in patients with an intact immune system an alternative approach to treating such infections would be to render the bacteria susceptible to natural immune clearance. We have identified a highly potent small molecule inhibitor of E. coli capsule biogenesis that targets a transcriptional regulator of an MDR efflux pump. This proposal centers on the hypothesis that this capsule inhibitor uniquely binds to the efflux pump transcriptional regulator to control E. coli polysaccharide capsule expression through a novel co-regulatory pathway that results in decreased virulence and increased susceptibility to the host immune system. This study will test the hypothesis by investigating the binding of capsule inhibitor to the transcriptional regulator, by identifying the components of the co-regulatory pathway and by determining the role of the transcriptional regulator in establishment and persistence of UTI. Dr. Seed will be providing mentorship and expertise in the field of molecular microbial pathogenesis, microbial genomics and the murine model of UTI. I have worked with Dr. Seed since 2011 as a pediatric infectious disease fellow and will continue to do so as junior faculty. Duke University is a world-class research institute with numerous support systems for junior investigators which will be vital for my transition to being an independent investigator. My long term career goal is to be independently funded leading my own lab focused on using molecular approaches to identify mechanisms of bacterial pathogenesis and antimicrobial resistance and to use this knowledge to identify novel targets for pathogen/disease-specific anti-infectives. This award will enable me to build upon the research foundation I have developed thus far and be exceptionally well poised to transition to independence.

项目总结