MOLECULAR EVOLUTION OF ENTERIC BACTERIOCINS

微生物正在进行一场永无止境的军备竞赛。这场微生物大战在很大程度上针对的是同种生物和近亲，它们在获取利基和营养资源方面竞争最激烈。这种激烈竞争的一个进化结果是大多数细菌产生的抗菌化合物的多样性。令人惊讶的是，人们很少注意了解这些化合物在自然微生物群落中扮演的角色或它们的进化。细菌素是一类抗菌素，由于细菌素多样性的惊人高水平，细菌素在细菌中的广泛分布，以及细菌素在食品工业中作为防腐剂和在人类健康工业中作为抗生素的使用，细菌素受到越来越多的关注。我们现在对细菌素介导的杀伤、细胞识别和细胞转运的分子机制有了复杂的理解。然而，很少有人致力于解决生态和进化问题，例如：这些毒素在调节微生物相互作用中起什么作用；这类异质蛋白质的起源和进化关系是什么；它们的多样化涉及什么分子机制；以及对这样一个武器库的进化反应是什么，即防御机制和由此产生的进化军备竞赛？这项研究建议的重点就是具体解决这些问题。我们建议提供细菌素产生的频率和分布以及在临床相关的细菌科，肠杆菌科的详细描述。然后，新的细菌素将被克隆和测序。这些数据将有助于我们确定细菌素作用的系统发育范围、自然产生的耐药性水平，以及确定肠道细菌素之间的进化关系及其多样化模式。本质上，我们提出的是探索细菌素的自然历史，以寻找更好的理解如何使用细菌素和其他相关的抗菌素来取代或补充经典的抗生素。我们对细菌素的自然作用的理解，以及在细菌群落中对细菌素的防御，可以直接应用于小说中抗菌素在人类健康问题上的合理应用。

Microbes are engaged in a never-ending arms race. This microbial warfare is directed in large part at conspecifics and close relatives with which they compete most intensively for access to niches and nutritional resources. One evolutionary consequence of this intense competition is the diversity of antimicrobial compounds that most species of bacteria produce. Surprisingly, there has been little attention paid to understanding either the role these compounds play in natural microbial communities or their evolution. One class of antimicrobials, the bacteriocins, has received increasing attention because of the surprisingly high levels of bacteriocin diversity observed, the widespread distribution of bacteriocins in bacteria, and the use of bacteriocins as preservatives in the food industry and as antibiotics in the human health industry. We now have a sophisticated understanding of the molecular mechanisms involved in bacteriocin-mediated killing, cell recognition and transport into the cell. However, very little effort has been focused on addressing ecological and evolutionary questions, such as: what role do these toxins play in mediating microbial interactions, what are the origins of and evolutionary relationships among this heterogeneous class of proteins, what molecular mechanisms are involved in their diversification, and what are the evolutionary responses to such an arsenal of weapons, i.e. the mechanisms of defense and the resulting evolutionary arms race? The focus of this research proposal is to specifically tackle these issues. We propose to provide a detailed description of the frequency and distribution of bacteriocin production and resistance in one clinically relevant, division of bacteria, the Enterobacteriaceae. Novel bacteriocins will then be cloned and sequenced. These data will help us to determine the phylogenetic range over which bacteriocins act, the levels of naturally occurring resistance, as well as determine the evolutionary relationships among enteric bacteriocins and their modes of diversification. In essence, what we propose is to explore the natural history of bacteriocins in search of a better understanding of how bacteriocins, and other related antimicrobials, can be used to replace, or supplement, classical antibiotics. The understanding that we gain regarding the natural role of bacteriocins, and the defenses raised against them within bacterial communities, can be directly applied to the rational application of novels antimicrobials to human health issues