The role of bacteriocins on S. pneumoniae diversity

虽然人类最近才将化学武器添加到其武器库中，但有毒物质数百万年来一直是细菌和真菌的首选武器。人类已经利用微生物制品，如青霉素和链霉素，来治疗细菌性疾病。自从弗莱明发现由青霉菌产生的青霉素以来，这些药物取得了巨大的成功，改变了医学景观，大大改善了人类健康。然而，抗微生物剂的微生物使用相当不友好。相反，微生物被认为是利用这些巨大的不同毒素来杀死对方，从而使生产菌株在争夺资源的斗争中占据一席之地。这种斗争是微生物生态学和进化的一个关键方面，对于生活在土壤中的微生物和那些作为病原体生活在人体内的微生物同样重要。最近的理论研究表明，产生不同毒素（称为细菌素）的细菌菌株之间的竞争可以导致几乎无限的细菌类型的进化，这些细菌类型产生不同的细菌素和细菌素抗性机制。因此，至少在理论上，一种菌株对另一种菌株的细菌军备竞赛与我们自己对它们的军备竞赛非常相似;在这两种情况下，新药都被开发出来（进化），而其他药物则由于耐药性的进化而失去效力。因此，这项提议的目的是了解细菌之间这种广泛的化学战争的进化原因和后果。为了实现这些目标，我们将采用一种策略，将新理论的发展与一种称为实验进化的方法相结合，该方法研究了实验室中数千代细菌的进化。我们的研究系统将基于革兰氏阳性病原体S产生的细菌素。肺炎。S.肺炎仍然是全世界儿童和老年人细菌性疾病的主要原因之一。该物种中的细菌素是高度多样化的，诱导它们的信号分子也是如此。信号和毒素的组合可能存在数百种不同的组合，其原因和后果是未知的。我们将使用以下计划来回答这些问题。首先，我们将描述S的多样性。通过在成对比赛中相互竞争菌株来提高肺炎毒素和耐药性。接下来，我们将通过对天然细菌菌株的相关基因进行测序，寻求了解毒性和抗性的遗传学。利用这些分析中获得的信息，我们将建立理论模型来模拟细菌多毒素群落的共同进化。我们将询问这些模型如何预测自然种群中毒性特征的实际多样性。此外，我们将使用该模型来生成有关合成细菌群落进化的新预测。最后，我们将通过允许细菌菌株的混合物在实验室中进化1,000代来测试这些预测。在这一阶段的进化之后，我们将研究竞争种群所积累的表型和遗传变化，我们的结果将有几个基本的和应用的意义。科学家们正在努力专门组装微生物群落，以提供健康和环境相关的服务。因此，对细菌病原体种群的控制规则进行集中和预测性的理解显然是相当重要的。此外，细菌素越来越多地被探索作为替代抗菌剂，并已被开发为食品防腐剂。S.肺炎正在增加，并且对替代化疗剂的需求是真实的。细菌素的成功部署依赖于对其多样性的理解以及细胞进化以抵抗它们的反应。

While mankind has only recently added chemical weapons to it's arsenal, toxic agents have been the weapons of choice for bacteria and fungi for millions of years. Humans have exploited microbial products, such as penicillin and streptomycin, to cure bacterial diseases. Since Fleming's discovery of penicillin, produced by the Penicillium mold, these drugs have worked with remarkable success, transforming the medical landscape and dramatically improving human health. The microbial use of antimicrobials, however, is considerably less friendly. Instead, microbes are believed to use these hugely diverse toxins to kill each other, thereby enabling producing strains to gain ground in the struggle for resources. This struggle is a key aspect of microbial ecology and evolution, equally important for microbes living in the soil and those living as pathogens within the human body. Recent theoretical studies have shown that competition between strains of bacteria producing different toxins, called bacteriocins, can cause the evolution of a nearly limitless variety of bacterial types that produce diverse bacteriocins and mechanisms of bacteriocin resistance. Thus, it appears, at least in theory, that the bacterial arms-race of one strain against another closely resembles our own arms-race against them; in both cases new drugs are developed (evolve) while others lose efficacy due to the evolution of resistance. The aims of this proposal are therefore to understand the evolutionary causes and consequences of this widespread chemical warfare between bacteria. To address these aims we will employ a strategy combining the development of new theory with an approach called experimental evolution, which examines the evolution of bacteria in the lab over thousands of generations. Our study system will be based upon bacteriocins produced by the gram-positive pathogen S. pneumoniae. S. pneumoniae remains one of the leading causes of bacterial diseases in children and the elderly worldwide. The bacteriocins in this species are highly diverse as are the signaling molecules that induce them. Hundreds of distinct combinations of signal and toxin can exist, the causes and consequences of which are unknown.We will use the following plan to answer these questions. First, we will characterize the diversity of S. pneumoniae toxins and resistance by competing strains against one another in pair-wise tournaments. We will next seek to understand the genetics of toxicity and resistance by sequencing the relevant genes from natural bacterial strains. Using the information gained in these analyses, we will build theoretical models to simulate the coevolution of multi-toxin communities of bacteria. We will ask how well these models predict the actual diversity of toxicity profiles in natural populations. In addition, we will use the model to generate novel predictions about evolution of synthetic bacterial communities. Finally, we will test these predictions by allowing mixtures of bacterial strains to evolve in the lab for 1,000s of generations. After this period of evolution we will study phenotypic and genetic changes that competing populations have accumulated.Our results will have several fundamental and applied implications. Scientists are working to specifically assemble microbial communites to perform heath and environment related services. It is thus clearly of considerable importance to develop a focused and predictive understanding of rules governing populations of bacterial pathogens. Furthermore, bacteriocins are increasingly being explored as alternative antimicrobials and have been developed as food preservatives. Antibiotic resistance in S. pneumoniae is increasing and the need for alternative chemotherapeutic agents is real. The successful deployment of bacteriocins relies on an understanding of their diversity and the responses cells evolve to resist them.