CYCLIC DI-GMP SIGNALING IN BACTERIAL PATHOGENESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 传染病仍然是全球主要的死亡原因之一，强调了目前治疗的局限性和对新方法的需求。近年来，已变得明显的是，细菌培养物也作为多细胞群落（所谓的生物膜）在感染中发挥毒力。大多数慢性感染可归因于生物膜，增加其致病性并有助于抗生素耐受性和耐药性的传播。生物膜的形成涉及信号传导过程，控制从自由游动、无张力状态到表面附着、自足的社会生命形式的转换。虽然生物膜特异性基因已被确定，该过程已被形态学研究，生物膜的形成是如何调节的，以及涉及的潜在信号传导机制，在很大程度上是未知的。我们研究了微生物世界中独特的第二信使，环状二GMP，最近已被证明可以控制分泌，细胞粘附和运动，导致生物膜形成和细胞毒性增加。负责催化环二GMP的合成和降解的蛋白质结构域，即GGDEF和EAL结构域，分别已在迄今为止测序的几乎每种真细菌基因组中大量鉴定。GGDEF和EAL结构域发生在不同的多结构域信号蛋白的背景下，并作为多组分信号系统的一部分，从而表明在感知环境线索中的作用。我们使用结构和功能方法研究这些关键开关在生物膜形成和细胞毒性中的酶促和调节机制。鉴于真核细胞中不存在c-di-GMP，我们设想这些信号系统可能为开发新型抗菌药物和调节生物膜形成的方法提供有吸引力的靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infectious diseases remain one of the leading causes of death worldwide, emphasizing the limitations of current treatments and the need for novel approaches. In recent years, it has become evident that bacterial cultures also exert virulence in infections as multi-cellular communities, so-called biofilms. The majority of chronic infections can be attributed to biofilms, increasing their pathogenicity and contributing to the spreading of antibiotic tolerance and resistance. The formation of biofilms involves signaling processes controlling the switch from a free-swimming, planktonic state to a surface-attached, self-contained social life form. Although biofilm-specific genes have been identified and the process has been studied morphologically, how biofilm formation is regulated, and the underlying signaling mechanisms involved, are largely unknown. We study a second messenger unique in the microbial world, cyclic di-GMP, that recently has been shown to control secretion, cell adhesion and motility leading to biofilm formation and increased cytotoxicity. The protein domains responsible for catalyzing the synthesis and degradation of cyclic di-GMP, namely GGDEF and EAL domains, respectively, have been identified in large numbers in almost every eubacterial genome sequenced to date. GGDEF and EAL domains occur in the context of diverse multi-domain signaling proteins, and as part of multi-component signaling systems, thus suggesting a role in sensing environmental cues. We study the enzymatic and regulatory mechanisms of these key switches in biofilm formation and cytotoxicity, using structural and functional approaches. Given the absence of c-di-GMP in eukaryotic cells, we envision that these signaling systems might provide attractive targets for the development of novel antibacterials and methods to modulate biofilm formation.