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: 8443269
• 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/8443269
• 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）： 感染性腹泻是由多种病毒、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，从每年造成约60万人死亡的严重疾病-肠热病，到每年影响100多万美国人的非伤寒性人畜共患感染，包括现役军人和退伍军人。沙门氏菌和医学上重要的革兰氏阴性杆菌的治疗通常由于病原菌对临床使用的抗生素的耐药性增加而复杂化。外排泵、修饰酶和改变的靶点增强了细菌对抗生素的耐药性。此外，抗生素治疗的有效性受到细菌细胞使用的代谢途径和生物体对环境应激的适应性反应的极大影响。我们实验室和其他实验室的最新研究表明，内源性或巨噬细胞先天性反应产生的一氧化氮在多种革兰氏阳性和阴性微生物中增强抗生素耐受性。一氧化氮引起的保护反应似乎与这种双原子自由基引起抗氧化反应的能力有关。 在他的申请中提出的初步数据已经鉴定了DksA球状结构域中的锌指作为氧化和亚硝化应激的真正传感器。我们推测，敏感的反应物种的DksA锌指促进抗氧化剂和抗硝化防御，抗生素耐药性和沙门氏菌的致病性。目的1将确定DksA锌指介导氧化和亚硝化应激的分子机制。目标2和3将确定DksA调控的严格反应和半胱氨酸生物合成如何促进沙门氏菌的毒力，抗氧化防御和抗生素耐受性。这些调查将提供深入了解沙门氏菌的抗氧化剂和抗亚硝化防御是至关重要的胞内生存和毒力。这项研究还将有助于合理开发未来的预防和治疗方法，用于治疗各种革兰氏阴性，通常是抗生素耐药的细菌，这些细菌导致地球仪人群的高发病率和死亡率，包括退伍军人和VA医院的患者。