Bacillus subtilis stress responses

项目摘要/摘要 细菌和人类有着复杂的关系：我们丰富的共生有机体 提供了许多好处，而致病菌造成了很大的发病率和负担 死亡率。免疫系统通过营养免疫、抗菌药物来限制细菌的生长 多肽、裂解酶和吞噬细胞。潜在的病原体对这些威胁的反应是 激活特定的适应性反应，其中许多对毒力至关重要。我们研究压力 模式革兰氏阳性菌枯草芽孢杆菌的反应。一个项目解决了对 必需的营养金属离子锌、铁和锰的有效性的变化。免疫者 系统通过金属隔离来限制病原体的生长，在组织中(例如通过钙保护素) 吞噬后。此外，吞噬细胞通过金属中毒杀死细胞。我们有 证明金属离子的动态平衡依赖于特定的金属感应转录因子 对铁(Fur和Perr)、锰(MntR)和锌(Zur和ChurA)的限制和过量做出反应。 我们将描述这些转录因子调控的基因，以及它们在金属中的作用 动态平衡，并确定由金属离子限制和 喝醉了。这项工作将建立在我们最近确定的两种铁的主要外流系统的基础上 还有锰。这些研究的洞察力将与类似的压力直接相关 存在于人类病原体中的反应。免疫系统也会限制病原体的生长。 通过产生抗菌肽和裂解酶，这两者都会影响细胞的完整性 信封。细胞膜也是我们许多最重要的抗生素的靶标。一秒钟内 项目中，我们已经在枯草杆菌中定义了几种不同的细胞膜应激反应，重点是 那些由替代的西格玛因子调节的。我们已经确定了一系列突变的基因 应激反应途径和对细胞敏感性升高的关键中枢代谢途径 墙面抗生素，包括至关重要的β-内酰胺类药物。此外，我们还进行了新的探索 发现了抗生素协同作用，可能对临床方法产生影响。精选 抗生素耐药抑制基因为阐明抗生素的基础提供了有力的途径 协同作用，以及特定的应激反应途径的作用。这些通路是细胞的中心 通常情况下，除了它们在感知和响应抗生素方面的作用外，包膜动态平衡- 诱导应激，并与抗生素耐药和耐药性的出现有关 病原体。

Project Summary/Abstract Bacteria and humans have a complex relationship: our abundant commensal organisms provide numerous benefits, whereas pathogenic bacteria impose a large burden of morbidity and mortality. The immune system restricts bacterial growth through nutritional immunity, antimicrobial peptides, lytic enzymes, and phagocytic cells. Potential pathogens respond to these threats by the activation of specific adaptive responses, many of which are critical for virulence. We study stress responses in Bacillus subtilis, a model Gram positive bacterium. One project addresses responses to the changing availability of the essential nutrient metal ions zinc, iron, and manganese. The immune system restricts the growth of pathogens by metal sequestration, both in tissues (e.g. by calprotectin) and after phagocytosis. In addition, phagocytic cells kill cells by metal intoxication. We have demonstrated that metal ion homeostasis relies on specific metal-sensing transcription factors that respond to limitation and excess of iron (Fur and PerR), manganese (MntR), and zinc (Zur and CzrA). We will characterize the genes regulated by these transcription factors, their roles in metal homeostasis, and identify the physiological effects that result from both metal ion limitation and intoxication. This work will build upon our recent identification of the major efflux systems for both iron and manganese. The insights from these studies will be directly relevant to the similar stress responses present in human pathogens. The immune system also restricts the growth of pathogens by production of antibacterial peptides and lytic enzymes, both of which affect the integrity of the cell envelope. The cell envelope is also a target for many of our most important antibiotics. In a second project, we have defined several distinct cell envelope stress responses in B. subtilis, with a focus on those regulated by alternative sigma factors. We have identified an array of mutants with alterations in stress response pathways and in key central metabolic pathways that have elevated sensitivity to cell wall antibiotics, including the critically important beta-lactams. In addition, we explore newly discovered antibiotic synergies with possible implications for clinical approaches. Selection of antibiotic resistant suppressors provides a powerful approach for delineating the basis of antibiotic synergies, and the roles of specific stress response pathways. These pathways are central to cell envelope homeostasis generally, in addition to their role in sensing and responding to antibiotic- induced stress, and are implicated in the emergence of antibiotic tolerance and resistance in pathogens.