Evolution of Stress-Induced Bacterial Toxins

压力引起的细菌毒素的演变

• 批准号: 7392864
• 负责人: Margaret A. Riley
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392864
• 关键词: Address; Anaerobiosis; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Bacterial Toxins; Bacteriocin Typing; Biological Assay; Cells; Cheese; Collection; Colon; Communities; Computer Simulation; Condition; DNA Damage; Data; Ecology; Enteral; Enterobacteriaceae; Environment; Environmental Risk Factor; Escherichia coli; Evolution; Family; Gene Expression; Genes; Genome; Genus Cola; Goals; Green Fluorescent Proteins; Habitats; Health; Human; Hydrogen Peroxide; In Vitro; Intestines; Investigation; Investments; Learning; Longevity; Mammals; Meat; Mediating; Mitomycin; Modeling; Molecular Weight; Monitor; Mus; Nature; Nucleic Acid Regulatory Sequences; Operon; Pharmaceutical Preparations; Pharmacologic Substance; Plasmids; Play; Population; Population Dynamics; Principal Investigator; Production; Proteins; Rate; Regulation; Regulatory Pathway; Relative (related person); Reporter; Repression; Research; Research Personnel; Resistance; Role; Role playing therapy; SOS Response; Signal Transduction; Silicon Dioxide; Son of Sevenless Proteins; Sorting - Cell Movement; Stress; Structure; Surveys; System; Temperature; Testing; Theoretical Studies; Therapeutic; Toxin; antimicrobial; bacteriocin; bile salts; colicin; design; in vivo; in vivo Model; killings; microbial; microbial community; microorganism interaction; model development; mouse model; nuclease; programs; promoter; research study; response; tool

DESCRIPTION (provided by applicant): Bacteriocins comprise a large, functionally diverse family of toxins often described as the microbial world's first choice in defense strategies. In contrast to the limited taxonomic distribution of classical antibiotic production, bacteriocins are produced by all bacterial lineages surveyed to date. Bacteriocins display a unique form of expression that is confined to stressful conditions and is lethal to the producing cell. Little is known about the mechanisms involved in this expression system. The goal of this proposal is to experimentally identify environmental biotic and a-biotic factors that play a role in colicin induction and to assess the impact of such production on the producing and target bacterial populations. The proposed combination of empirical and theoretical studies will provide the first comprehensive investigation into the ecological role and dynamics of bacteriocin production and the resulting impact of toxin expression on the population dynamics of the target bacteria. These data are both timely and critical from a human health perspective. If we have learned anything from our overuse of classical antibiotics, it is that as we artificially increase the presence of these naturally occurring antimicrobials, the bacterial communities rapidly respond with the evolution of antibiotic resistance. Drugs that required 10+ years of research and up to a billion dollars investment are rendered useless in short order. If we had invested in a thorough investigation into the natural roles played by classical antibiotics and the resulting responses of the microbial community to their presence, we might have designed therapeutic approaches that would have limited the rate and the scope of resistance evolution and thus extended the lifespan of these critical drugs. Bacteriocins are already used as preservatives in certain meats and cheeses and are currently being tested for use in the treatment of a variety of bacterial infections. The widespread use of these potent, narrow spectrum drugs is rapidly approaching. We need to know NOW how to advise pharmaceutical companies and clinicians how best to deploy these potent toxins in a manner that will retain their utility for as long as is possible. The experiments proposed here will provide exactly the sort of information required to make informed decisions about how and when to employ bacteriocins in therapeutic treatment and will allow us to make predictions as to the likely response by the bacterial community.

描述（由申请人提供）：细菌素包括一个庞大的、功能多样的毒素家族，通常被描述为微生物界防御策略的首选。与经典抗生素生产的有限分类学分布相反，细菌素由迄今为止调查的所有细菌谱系产生。细菌素表现出一种独特的表达形式，仅限于应激条件下，对生产细胞是致命的。关于这个表达系统的机制知之甚少。本提案的目标是通过实验确定在大肠杆菌素诱导中发挥作用的环境生物和非生物因素，并评估这种生产对生产和目标细菌种群的影响。建议的经验和理论研究相结合，将提供第一次全面调查的生态作用和细菌素生产的动态和毒素表达对目标细菌的种群动态的影响。从人类健康的角度来看，这些数据既及时又重要。如果说我们从过度使用经典抗生素中学到了什么，那就是当我们人为地增加这些天然存在的抗生素的存在时，细菌群落会迅速对抗生素耐药性的进化做出反应。需要10年以上研究和高达10亿美元投资的药物在短时间内变得毫无用处。如果我们对经典抗生素所起的自然作用以及微生物群落对它们的存在所产生的反应进行了彻底的调查，我们可能会设计出限制耐药性演变的速度和范围的治疗方法，从而延长这些关键药物的寿命。细菌素已经被用作某些肉类和奶酪的防腐剂，目前正在测试用于治疗各种细菌感染。这些有效的窄谱药物的广泛使用正在迅速接近。我们现在需要知道如何建议制药公司和临床医生如何最好地部署这些强效毒素的方式，将保持其效用尽可能长的时间。这里提出的实验将提供确切的信息，以便就如何以及何时在治疗中使用细菌素做出明智的决定，并使我们能够预测细菌群落可能的反应。