The chemical and genetic basis of interspecies interactions

描述(由申请人提供)： 枯草芽孢杆菌产生广泛的胞外代谢物，可以抑制细菌和真菌的生长，或者改变它们的行为，以减少潜在危险邻居产生的抗菌产品。我们建议使用成像质谱学和经典分析化学的新技术来系统地鉴定枯草杆菌的胞外代谢组，重点是表征由其他细菌诱导的相互作用的代谢组。我们将研究这些化合物在枯草杆菌与其他物种相互作用的两个不同结果中所起的作用。第一个是僵局，枯草杆菌与其他产生各种抗菌化合物的物种(如铜绿假单胞菌)形成紧密毗邻的群体。第二种更频繁的行为是接触依赖的捕食，即枯草杆菌向邻近殖民地移动，入侵并摧毁邻近殖民地，导致被捕食物种死亡，并扩大枯草杆菌群体的领土。这些可复制的行为在不同的未驯化枯草杆菌菌株中是保守的。我们将确定这些行为是否依赖于相互作用的代谢组，并调查单个化合物对靶细胞活性和行为的影响。我们将进一步研究物种间相互作用的遗传要求，以确定导致这些不同结果的应激反应、发育和生物合成途径，并将使用荧光显微镜观察物种间相互作用的细胞后果。这些研究将阐明物种间相互作用的机制基础，并识别影响其他物种生存能力或行为的次生代谢物，以代表潜在的新抗菌药物。 公共卫生相关性： 细菌产生许多胞外代谢物来调节它们与其他物种的相互作用，其中许多具有抗菌和抗真菌活性。我们将在这里阐明这些分子允许枯草芽孢杆菌与其他细菌物种相互作用的化学、遗传和细胞机制，产生从共存到入侵和破坏邻近菌落的各种结果。物种间的相互作用在医学上是至关重要的，促进破坏其他物种的代谢物代表着有希望的新的药物线索。

DESCRIPTION (provided by applicant): Bacillus subtilis produces a wide array of extracellular metabolites that can inhibit the growth of bacteria and fungi or modify their behavior to attenuate the production of antibacterial products by potentially dangerous neighbors. We here propose to use the new technique of imaging mass spectrometry and classical analytical chemistry to systematically identify the extracellular metabolome of B. subtilis, with a focus on characterizing the interactive metabolome that is induced by other bacterial species. We will investigate the role these compounds play in two distinct outcomes of the interaction of B. subtilis with other species. The first is an impasse, in which B. subtilis forms closely abutting colonies with other species that produce a variety of antibacterial compounds (such as P. aeruginosa). The second, more frequent behavior is contact-dependent predation, in which B. subtilis moves towards, invades and destroys neighboring colonies, leading to death of the prey species and expanding the territory of the B. subtilis colony. These reproducible behaviors are conserved in different undomesticated B. subtilis strains. We will determine if these behaviors depend on the interactive metabolome and investigate the effects individual compounds have on target cell viability and behavior. We will further investigate the genetic requirements for interspecies interactions to identify stress responses, developmental and biosynthetic pathways that contribute to these distinct outcomes and we will use fluorescence microscopy to visualize the cellular consequences of interspecies interactions. These studies will illuminate the mechanistic basis for interspecies interactions and identify secondary metabolites that affect viability or behavior of other species that represent potential new antibacterial drugs. PUBLIC HEALTH RELEVANCE: Bacteria produce many extracellular metabolites that mediate their interaction with other species, many of which have antibacterial and antifungal activities. We will here elucidate the chemical, genetic and cellular mechanisms by which these molecules allow Bacillus subtilis to interact with other bacterial species, producing outcomes ranging from coexistence to the invasion and destruction of neighboring colonies. Interspecies interactions are critical in medicine and the metabolites that facilitate destruction of other species represent promising new pharmaceutical leads.