Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species

细菌对宿主反应物种适应性反应的分子分析

• 批准号: 10382226
• 负责人: Andres Vazquez-Torres
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382226
• 关键词: Aminoglycoside Antibiotics; Aminoglycoside resistance; Aminoglycosides; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antioxidants; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Blood; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinic; Clinical; DNA-Directed RNA Polymerase; Data; Development; Diarrhea; Family; Future; Gastroenteritis; Gene Cluster; General Population; Genetic Transcription; Goals; HIV; Hospitals; Human; Individual; Inflammation Mediators; Investigation; Knowledge; Laboratories; Life; Life Style; Mediating; Medical; Military Personnel; Molecular; Molecular Analysis; Molecular Chaperones; Molecular Target; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; NADPH Oxidase; Oxidative Stress; Oxides; Oxidoreductase; Pathogenesis; Pathogenicity Island; Patients; Persons; Plague; Play; Poison; Proteins; RNA; Regulation; Research; Resistance; Role; Salmonella; Salmonella enterica; Secondary to; Sum; Syndrome; Testing; Therapeutic; Transcription Elongation; Transcriptional Activation; Transcriptional Regulation; Translations; Type III Secretion System Pathway; Veterans; Virulence; Woman; Work; World Health Organization; antibiotic tolerance; antimicrobial; attenuation; bactericide; clinically relevant; drug resistant bacteria; fight against; global health; human pathogen; men; mortality; mutant; non-typhoidal Salmonella; novel; novel therapeutics; nucleoside triphosphate; pathogen; pathogenic bacteria; programs; prophylactic; response

Infectious diarrhea afflicts a billion people a year and is responsible for approximately 4% of all human deaths worldwide. Salmonella enterica are common causes of infectious diarrhea in humans, and often plague active military servicemen and veterans. Salmonella are among the most frequent bacterial isolates resistant to antibiotics. The antibiotic resistance crisis is becoming a clinical problem of epic proportions, as the number of therapeutic compounds in the pipeline is dwindling. Future prophylactic and therapeutic approaches against drug resistant bacteria will greatly benefit from the identification of molecular targets in pathogens. During the last 20 years only 4 novel compounds have been introduced in the clinic, all of which represent new mechanisms identified through basic understanding of molecular pathogenesis. As holds true for all human pathogens, precise regulation of RNA polymerase controls essential aspects of Salmonella pathogenesis, and the expression of antibiotic resistant programs. Our investigations have shown that allosteric interactions of DksA and Gre factors with RNA polymerase regulate vital facets of Salmonella pathogenesis and antibiotic resistance. The proposed research will elucidate the mechanisms by which the DnaK/DnaJ chaperone couple regulates interactions of DksA with RNA polymerase, thereby engaging fundamental Salmonella virulence programs. We will also characterize how binding of Gre factors to the secondary channel of RNA polymerase provides a previously unsuspected level of regulation of Salmonella pathogenesis and antibiotic tolerance. Specifically, we will test the role that the transcriptional proofreading associated with Gre factors plays in resistance of Salmonella to the bactericidal activity inherent to the NADPH oxidase. Our investigations will also characterize how Gre factors modulate the expression of a type III secretion system that is vital to the intracellular lifestyle of Salmonella, while bolstering resistance to aminoglycoside antibiotics that poison bacterial translation. Our investigations will aid in the rational development of future therapies against a variety of Gram-negative, antibiotic resistant bacteria that cause high rates of morbidity and mortality in active servicemen, veterans and their families.

感染性腹泻每年折磨着10亿人，占人类总死亡人数的约4%。 全球死亡。肠道沙门氏菌是人类感染性腹泻的常见原因， 折磨着现役军人和退伍军人沙门氏菌是最常见的细菌 对抗生素有抗药性的菌株抗生素耐药性危机正在成为一个临床问题的史诗 比例，因为管道中的治疗化合物的数量正在减少。未来预防 和针对耐药细菌的治疗方法将极大地受益于鉴定 病原体中的分子靶点。在过去的20年里，只有4种新化合物被引入 在临床上，所有这些都代表了通过对分子生物学的基本理解而确定的新机制。 发病机制正如所有人类病原体一样，RNA聚合酶的精确调节控制着 沙门氏菌发病机理的基本方面，以及抗生素耐药程序的表达。我们 研究表明DksA和Gre因子与RNA聚合酶的变构相互作用 调节沙门氏菌发病机制和抗生素耐药性的重要方面。拟议的研究将 阐明DnaK/DnaJ伴侣对调节DksA相互作用的机制 与RNA聚合酶，从而从事基本沙门氏菌毒力计划。我们还将 表征Gre因子与RNA聚合酶的二级通道的结合如何提供 沙门氏菌发病机制和抗生素耐受性的调节水平以前未被怀疑。 具体来说，我们将测试与Gre因子相关的转录校对在 沙门氏菌对NADPH氧化酶固有的杀菌活性的抗性。我们的调查 还将描述Gre因子如何调节III型分泌系统的表达， 沙门氏菌的细胞内生活方式，同时支持对氨基糖苷类抗生素的耐药性， 毒细菌翻译。我们的研究将有助于未来疗法的合理发展 针对各种革兰氏阴性、抗生素耐药细菌，这些细菌导致高发病率， 现役军人、退伍军人及其家属的死亡率。