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Integration of heme acquisition and signaling in Gram-negative pathogens

革兰氏阴性病原体中血红素获取和信号传导的整合

基本信息

批准号：
10772354
负责人：
Amanda Gail Oglesby
金额：
$ 6.32万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10772354
关键词：
Accounting Aerobic Affect Anti-Bacterial Agents Antibiotic Resistance Bacterial Infections Binding Binding Proteins Biochemical Biological Process Biophysics Cells Cessation of life Citric Acid Cycle Cytoplasm DNA DNA biosynthesis Data Drug resistance EMSA ESKAPE pathogens Event Fluorescence Anisotropy Future Gene Expression Genes Genetic Genetic Transcription Genetic study Goals Heme Homeostasis Homologous Gene Infection Iron Klebsiella pneumoniae Laboratories Life Link Membrane Metabolism Methods Microbial Biofilms Micronutrients Molecular Mutation Mycoses Oxidation-Reduction Oxidative Stress Oxygenases Peptide Hydrolases Post-Transcriptional Regulation Property Proteins Proteomics Pseudomonas aeruginosa Public Health RNA RNA Binding RNA chemical synthesis Regulation Regulon Reporting Respiration Role Shigella dysenteriae Siderophores Signal Transduction Site-Directed Mutagenesis System Testing Time Toxin Transcriptional Regulation Up-Regulation Uropathogenic E. coli Variant Virulence Virulence Factors antimicrobial antimicrobial resistant pathogen antitermination biochemical tools biophysical techniques biophysical tools chronic infection constitutive expression enteric pathogen extracellular genetic regulatory protein heme-binding protein human pathogen in vivo innovation mRNA Transcript Degradation microorganism new therapeutic target novel therapeutic intervention pathogen pathogenic bacteria pathogenic microbe posttranscriptional promoter receptor rho trait transcription regulatory network uptake

项目摘要

PROJECT SUMMARY ESKAPE pathogens are a leading cause of drug resistant infections and the need to identify new antibacterial strategies is critical. Iron is an essential micronutrient for survival and virulence that microbial pathogens which actively sequesters iron away from microorganisms. Pathogens overcome this iron limitation through a variety of mechanisms, including the synthesis and secretion of siderophores that scavenge ferric (Fe3+) iron, the uptake of ferrous (Fe2+) iron via Feo or NRAMP-like systems, and acquisition of iron from host heme. iron acquisition and homeostasis by microbial pathogens is multifactorial and dependent on sophisticated transcriptional and post-transcriptional regulatory networks. We have recently shown the PhuS cytoplasmic heme binding protein has a dual function in regulating heme flux through HemO, and in the transcriptional regulation of the iron and heme regulated sRNA’s PrrF and PrrH. The PrrF sRNAs bind to complementary sequences of their target RNAs causing the RNAseE and Hfq-dependent mRNA degradation of genes involved in iron-storage and oxidative stress, aerobic and anaerobic metabolism, including iron containing proteins of the TCA cycle, as well as several virulence factors. Therefore, regulation of the heme flux through HemO is a critical link between heme metabolism and the iron-dependent sRNA regulatory network required for adaptation and virulence within the host. The goal of the proposal is to understand at a molecular level how heme acquisition is integrated into these regulatory networks. Specifically, we will; i) determine the PhuS structural motifs required for heme transfer and binding to the prrF1 promoter (PprrF1), ii) define the in vivo effects of PhuS variants on PrrF/H sRNAs and the downstream regulon. and iii) determine evolutionary conservation and function of PhuS homologs across enteric pathogens. On completion of the studies we will have determined the role of extracellular heme metabolism in the iron-dependent regulatory networks of three significant human pathogens, providing a platform for the identification of antibacterial strategies at the interface between of iron homeostasis and virulence.

项目总结