Conserved Proteus mirabilis genetic requirements for colonization of the catheterized urinary tract

导尿管定植的保守奇异变形杆菌遗传要求

基本信息

批准号：
10733307
负责人：
Chelsie Elizabeth Armbruster
金额：
$ 6.64万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733307
关键词：
Address Amino Acids Animal Model Antibiotic Resistance Antibiotic Therapy Bacteremia Bacteria Bladder Blood Circulation Catheterization Catheters Cells Cessation of life Clinical Data Defense Mechanisms Development Disease Drug Metabolic Detoxication Drug resistance Enterococcus Enterococcus faecalis Enzymes Escherichia coli Exposure to Extended-spectrum β-lactamase Future Genes Genetic Genome Gram-Negative Bacteria Growth Health Hospitals Human Hydrogen Peroxide Immune In Vitro Incubated Indwelling Catheter Infection Infection prevention Inflammation Intervention Invaded Kidney Knowledge Length of Stay Libraries Licensing Life Measures Mediating Metabolic Pathway Metabolism Mission Modeling Morganella morganii Multi-Drug Resistance Mus Organism Oxidative Stress Pathogenicity Pathway interactions Patients Peroxides Physiological Prevention Process Production Proteus mirabilis Providencia Reactive Oxygen Species Reporting Research Respiratory Burst Risk Role Sampling Serine Site Testing Therapeutic Intervention United States National Institutes of Health Urinary Calculi Urinary Catheterization Urinary tract Urine Uropathogen Vaccines Validation adverse outcome alkyl hydroperoxide reductase amino acid metabolism antimicrobial bacterial fitness carbapenemase catalase catheter associated UTI clinically relevant co-infection disorder prevention drug resistant bacteria effective therapy fitness functional decline gene conservation genome-wide health care settings healthcare-associated infections in vivo interest metabolic fitness mortality mouse model multi-drug resistant pathogen mutant neutrophil novel novel strategies preference prevent renal damage response urinary

项目摘要

Project Summary/Abstract Patients with indwelling urinary catheters have nearly double the mortality rate compared to non-catheterized patients due to the propensity for adverse outcomes, including functional decline, increased length of stay in hospital settings, catheter-associated urinary tract infections (CAUTI), and bacteremia. Catheterization also increases the likelihood of colonization by multidrug-resistant organisms, and antibiotic resistance is increasing at an alarming rate, making it imperative to identify novel, non-antibiotic treatments for CAUTI and associated complications. The Gram-negative bacterium Proteus mirabilis is a predominant cause of CAUTI, particularly during long-term catheterization. CAUTI is also frequently polymicrobial, which can increase risk of severe disease and bacteremia. There is, however, a fundamental gap in knowledge regarding conserved targets for treating or preventing disease due to P. mirabilis, particularly during polymicrobial infection. Our preliminary data clearly demonstrates that the presence of other bacterial species during infection dramatically impacts the genes required by P. mirabilis for colonization and persistence during CAUTI, especially the metabolic pathways that are favored by the bacterium for growth and the defense mechanisms that are used to evade host antimicrobial responses. However, we have uncovered a set of 217 genes encoded by P. mirabilis that provide a fitness advantage during single-species infection and polymicrobial infection with another Gram-negative bacterium, Providencia stuartii. Fifty-seven percent of these genes (123/217) are highly conserved in all 106 publically- available P. mirabilis genomes. The central hypothesis of this proposal is that P. mirabilis encodes a core set of conserved genes that are critical for establishing CAUTI, regardless of which other bacterial species are present. We further anticipate that a subset of these factors will be ideal targets for treatment or prevention of disease. This hypothesis will be tested through three concurrent specific aims. In Aim 1, we will utilize genome- wide transposon insertion-site sequencing to uncover the impact of co-colonization by two common uropathogens (Escherichia coli and Enterococcus faecalis) on the genes required by P. mirabilis to colonize the catheterized urinary tract, including which of the 123 conserved core fitness factors remain important for establishing infection and whether they are expressed during human CAUTI. In Aims 2 and 3, we will explore the importance of two pathways that are well-represented in the current set of core fitness factors (amino acid metabolism and peroxide detoxification) to P. mirabilis pathogenicity. This includes broad characterization of amino acid availability within the murine urinary tract, with or without an indwelling catheter, and the amino acid preferences of 5 uropathogens, as well as production of reactive oxygen species by these uropathogens and by neutrophils in response to the uropathogens. The knowledge gained herein will uncover unique challenges that the catheterized urinary tract presents to invading uropathogens, as well as novel, conserved, clinically-relevant targets for treating or preventing infections due to these prevalent and increasingly drug-resistant bacteria.

项目摘要/摘要与未进行的无导管的患者相比患者由于不良后果的倾向，包括功能性下降，停留时间增加医院环境，与导管相关的尿路感染（CAUTI）和菌血症。导管插入也是如此增加了抗多药的生物的定植可能性，抗生素耐药性正在增加以惊人的速度，必须确定针对小肠和相关的新型非抗生素治疗并发症。革兰氏阴性细菌mirabilis是cauti的主要原因，特别是在长期导管插入期间。 cauti也经常是多数菌，这可能会增加严重的风险疾病和菌血症。但是，关于保守目标的知识存在基本差距治疗或预防因奇异性疟原虫而引起的疾病，特别是在多虫病感染期间。我们的初步数据清楚地表明，感染过程中其他细菌物种的存在极大地影响了基因 Mirabilis要求在小捕虫期间定植和持久性，尤其是代谢途径受到生长细菌的青睐和用于逃避宿主抗菌抗菌的防御机制回答。但是，我们发现了一组由P. mirabilis编码的217个基因，这些基因提供了适合度单物种感染和多粒阴性细菌的多种物种感染期间的优势， Providencia Stuartii。这些基因中有百分之五十七（123/217）在所有106个公共中都高度保守可用的P. mirabilis基因组。该提议的中心假设是Mirabilis编码核心集对于建立cauti至关重要的保守基因，无论其他细菌种类是什么展示。我们进一步预期，这些因素的子集将是治疗或预防的理想目标疾病。该假设将通过三个并发的特定目的进行检验。在AIM 1中，我们将利用基因组 - 广泛的转座插入点测序，以发现两个共同的共殖化的影响 Mirabilis所需的基因上的尿道病（大肠杆菌和肠球菌粪便）才能定居导管尿路，包括123个保守的核心适应性因素中的哪个对建立感染以及它们是否在人类cauti期间表达。在目标2和3中，我们将探索在当前一组核心适应性因子（氨基酸）中有很好代表的两种途径的重要性代谢和过氧化解毒）至mirabilis致病性。这包括广泛的表征鼠尿路内的氨基酸供应性，有或没有留置导管，氨基酸和氨基酸 5种尿道病的偏好，以及这些尿道病和通过嗜中性粒细胞响应尿道病。本文获得的知识将发现独特的挑战导管尿路呈现以入侵尿道病，以及新颖的，保守的，临床上的相关性由于这些普遍且越来越多的药物抗性细菌，治疗或预防感染的靶标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential Contribution of Hydrogen Metabolism to Proteus mirabilis Fitness during Single-Species and Polymicrobial Catheterized Urinary Tract Infection.

DOI：
10.3390/pathogens12121377
发表时间：
2023-11-22
期刊：
Pathogens (Basel, Switzerland)
影响因子：
0
作者：
Brauer AL;Learman BS;Armbruster CE
通讯作者：
Armbruster CE

Preferential catabolism of l- vs d-serine by Proteus mirabilis contributes to pathogenesis and catheter-associated urinary tract infection.

DOI：
10.1111/mmi.14968
发表时间：
2022-09
期刊：
MOLECULAR MICROBIOLOGY
影响因子：
3.6
作者：
Brauer, Aimee L.;Learman, Brian S.;Taddei, Steven M.;Deka, Namrata;Hunt, Benjamin C.;Armbruster, Chelsie E.
通讯作者：
Armbruster, Chelsie E.