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: 8666538
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666538
• 关键词: Affect; American; Anabolism; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Antioxidants; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Caring; Cells; Cessation of life; Clinic; Clinical; Communities; Complex; Cysteine; DNA-Directed RNA Polymerase; Data; Development; Diarrhea; Disease; Effectiveness; Enteral; Enzymes; Eubacterium; Fostering; Future; Gastroenteritis; Genetic Transcription; Goals; Gram-Negative Bacteria; Guanine; HIV Infections; Hospitals; Host Defense; Human; Individual; Infection; Inflammation Mediators; Investigation; Laboratories; Life; Mediating; Metabolic Pathway; Military Personnel; Molecular; Molecular Analysis; Morbidity - disease rate; Mycoses; NADP; Nitric Oxide; Nitrogen; Nutritional; Organism; Oxidases; Oxidative Stress; Oxygen; Parasites; Parasitic infection; Pathogenesis; Pathogenicity; Patients; Phagocytes; Play; Population; Pseudomonas aeruginosa; Research; Resistance; Role; Salmonella; Salmonella enterica; Salmonella infections; Stress; Syndrome; Systemic disease; Systemic infection; Testing; Therapeutic; Typhoid Fever; Veterans; Vibrio cholerae; Virulence; Virus; Virus Diseases; Woman; Work; Zinc Fingers; Zoonotic Infection; arm; bone; clinically relevant; deprivation; efflux pump; fungus; genetic regulatory protein; human NOS2A protein; insight; killings; macrophage; men; microorganism; mortality; nitrosative stress; novel; pathogen; pathogenic bacteria; prophylactic; public health relevance; response; retinal rods; sensor

DESCRIPTION (provided by applicant): Infectious diarrhea is a complex syndrome caused by many viruses, parasites, fungi and bacteria such as Salmonella. Salmonellosis itself encompasses a spectrum of clinical diseases that range from enteric fever, a serious condition that kills about 600,000 people a year, to non-typhoidal zoonotic infections that affect more than a million Americans annually, including active military servicemen and the veteran population. Treatment of Salmonella and medically important Gram- negative rods is often complicated by the increasing resistance of pathogenic bacteria to the antibiotics used in the clinic. Efflux pumps, modifying enzymes, and altered targets enhance bacterial resistance to antibiotics. In addition, the effectiveness of antibiotic therapy is greatly influenced by the metabolic pathways used by the bacterial cell and by the adaptive responses of the organism to environmental stresses. Recent investigations from our laboratory and others have shown that nitric oxide produced endogenously or in the innate response of macrophages elicits antibiotic tolerance in a variety of Gram-positive and -negative microorganisms. The protective response elicited by nitric oxide appears to be associated the ability of this diatomic radical to elicit antioxidative responses. Preliminary data presented in his application has identified the zinc finger in the globular domain of DksA as a bone fide sensor of oxidative and nitrosative stress. We hypothesize that sensing of reactive species by the DksA zinc finger promotes antioxidant and antinitrosative defenses, antibiotic resistance and the pathogenicity of Salmonella. Aim 1 will determine the molecular mechanisms that mediate sensing of oxidative and nitrosative stress by the DksA zinc finger. Aims 2 and 3 will identify how DksA-regulated stringent response and cysteine biosynthesis foster Salmonella virulence, antioxidant defenses and antibiotic tolerance. These investigations will provide profound insights into the antioxidant and antinitrosative defenses of Salmonella that are critical for intracellula survival and virulence. This research will also help in the rational development of future prophylactic and therapeutic approaches for the treatment of a variety of Gram-negative, often antibiotic resistant, bacteria that cause high rates of morbidity and mortality in people around the globe, including veterans and patients in VA hospitals.

描述（由申请人提供）： 传染性腹泻是由许多病毒，寄生虫，真菌和细菌（如沙门氏菌）引起的复杂综合征。沙门氏菌病本身包括一系列临床疾病，范围从肠烧发烧，每年杀死约60万人的严重疾病，到每年影响超过一百万美国人的非细人动物感染，包括活跃的军事服务人员和退伍军人。致病细菌对临床中使用的抗生素的抗药性增加，沙门氏菌和医学上重要的革兰氏阴性棒通常会变得复杂。外排泵，修饰酶和改变靶标可以增强对抗生素的细菌耐药性。此外，抗生素疗法的有效性受到细菌细胞使用的代谢途径以及生物体对环境胁迫的自适应反应的极大影响。我们实验室和其他人的最新研究表明，一氧化氮是内源性产生的，或者在巨噬细胞的先天反应中引起了各种革兰氏阳性和阴性微生物的抗生素耐受性。一氧化氮引起的保护反应似乎与该双原激体产生抗氧化反应的能力相关联。 他的应用中介绍的初步数据已将DKSA球状结构域的锌指确定为氧化和硝化应激的骨骼传感器。我们假设DKSA锌指对反应性物种的传感促进了抗氧化剂和抗抗抗药性防御，抗生素耐药性和沙门氏菌的致病性。 AIM 1将确定DKSA锌指介导氧化和亚硝化应激感测的分子机制。目标2和3将确定DKSA调节的严格反应和半胱氨酸生物合成如何促进沙门氏菌毒力，抗氧化剂防御和抗生素耐受性。这些研究将为沙门氏菌的抗氧化剂和抗抗毒素防御能力提供深刻的见解，这些防御对于尿路内生存和毒力至关重要。这项研究还将有助于对未来预防性和治疗方法的合理发展，以治疗各种革兰氏阴性，通常是抗生素耐药性的细菌，这些细菌在全球范围内引起高度的发病率和死亡率，包括VA医院的退伍军人和患者。