Evolution of Stress-Induced Bacterial Toxins

压力引起的细菌毒素的演变

• 批准号: 7846522
• 负责人: Margaret A. Riley
• 金额: $ 5.24万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846522
• 关键词: Address; Anaerobiosis; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Bacterial Toxins; Bacteriocin Typing; Biological Assay; Cells; Cheese; Collection; Colon; Communities; Computer Simulation; DNA Damage; Data; Ecology; Enteral; Enterobacteriaceae; Environment; Environmental Risk Factor; Escherichia coli; Evolution; Family; Gene Expression; Genes; Goals; Habitats; Health; Human; Hydrogen Peroxide; In Vitro; Intestines; Investigation; Investments; Learning; Longevity; Mammals; Meat; Mediating; Mitomycins; Modeling; Molecular Weight; Monitor; Mus; Nature; Nucleic Acid Regulatory Sequences; Operon; Pharmaceutical Preparations; Pharmacologic Substance; Plasmids; Play; Population; Population Dynamics; Principal Investigator; Production; Proteins; Regulation; Regulatory Pathway; Relative (related person); Reporter; Reporter Genes; Repression; Research; Research Personnel; Resistance; Role; 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; genome-wide; 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）：细菌素包括一个大的，功能多样的毒素家族，通常被描述为微生物世界防御策略的首选。与传统抗生素生产的有限分类分布相反，细菌素是由迄今为止调查的所有细菌谱系产生的。细菌素表现出一种独特的表达形式，这种表达仅限于应激条件下，对产生细菌的细胞是致命的。我们对这一表达系统所涉及的机制知之甚少。本提案的目的是通过实验确定在大肠杆菌素诱导中起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。实验和理论研究的结合将首次全面研究细菌素产生的生态作用和动态，以及毒素表达对目标细菌种群动态的影响。从人类健康的角度来看，这些数据既及时又至关重要。如果我们从对经典抗生素的过度使用中学到了什么，那就是当我们人为地增加这些天然抗菌素的存在时，细菌群落会迅速做出反应，进化出抗生素耐药性。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无用。如果我们对经典抗生素的自然作用和微生物群落对它们的反应进行彻底的调查，我们可能已经设计出了治疗方法，可以限制耐药性进化的速度和范围，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的用途。这些强效、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向制药公司和临床医生提供建议，如何以尽可能长时间保持效用的方式最好地部署这些强效毒素。这里提出的实验将提供准确的信息，以做出明智的决定，决定如何以及何时在治疗中使用细菌素，并使我们能够预测细菌群落的可能反应。