Evolution of Stress-Induced Bacterial Toxins

描述(申请人提供)：细菌素包括一个大的、功能多样化的毒素家族，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不同，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，仅限于应激条件下，对产生细胞是致命的。对该表达系统涉及的机制知之甚少。这项建议的目标是通过实验确定在粘菌素诱导中起作用的环境生物和非生物因素，并评估这种生产对产生和目标细菌种群的影响。拟议的经验和理论研究相结合将首次全面调查细菌素生产的生态作用和动态，以及由此产生的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。如果说我们从过度使用经典抗生素中学到了什么的话，那就是当我们人为地增加这些自然产生的抗菌素的存在时，细菌群落会迅速对抗生素耐药性的进化做出反应。需要10年的研究和高达10亿美元的投资的药物很快就变得毫无用处。如果我们投资于彻底调查经典抗生素的自然作用以及由此产生的微生物群落对它们存在的反应，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。细菌素已经在某些肉类和奶酪中用作防腐剂，目前正在测试用于治疗各种细菌感染。这些强效、窄谱药物的广泛使用正在迅速到来。我们现在需要知道如何为制药公司和临床医生提供建议，如何以尽可能长的时间保持其效用的方式最好地部署这些有效的毒素。这里提议的实验将提供所需的信息，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。

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.