Bacillus subtilis stress responses

枯草芽孢杆菌应激反应

• 批准号: 10329263
• 负责人: John D Helmann
• 金额: $ 78.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329263
• 关键词: Address; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus subtilis; Bacteria; Biological Models; Cell Wall; Cells; Clinical; Complex; Environment; Enzymes; Genes; Gram-Positive Bacteria; Growth; Homeostasis; Human; Immune system; Innate Immune System; Intoxication; Invaded; Ions; Iron; Leukocyte L1 Antigen Complex; LytA enzyme; Manganese; Metabolic Pathway; Metals; Modeling; Morbidity - disease rate; Nutrient; Nutritional Immunity; Organism; Pathway interactions; Peptides; Phagocytes; Phagocytosis; Physiological; Production; Role; Sigma Factor; Stress; System; Tissues; Virulence; Work; Zinc; antibiotic tolerance; antimicrobial peptide; beta-Lactams; biological adaptation to stress; cell envelope; cell killing; human pathogen; insight; mortality; mutant; pathogen; pathogenic bacteria; response; synergism; transcription factor

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.

项目总结/摘要 细菌和人类有着复杂的关系：我们丰富的浮游生物 提供了许多益处，而病原菌造成了很大的发病负担， mortality.免疫系统通过营养免疫、抗微生物免疫和抗微生物免疫来限制细菌生长。 肽、溶解酶和吞噬细胞。潜在的病原体对这些威胁作出反应， 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 枯草芽孢杆菌（一种革兰氏阳性菌模型）中的反应。一个项目涉及对以下问题的回应： 必需营养金属离子锌、铁和锰的变化。免疫 系统通过金属螯合限制病原体的生长，包括在组织中（例如通过钙卫蛋白） 和吞噬作用后。此外，吞噬细胞通过金属中毒杀死细胞。我们有 证明了金属离子稳态依赖于特定的金属敏感转录因子， 对铁（Fur和PerR）、锰（MntR）和锌（Zur和CzrA）的限制和过量作出反应。 我们将描述由这些转录因子调控的基因，它们在金属代谢中的作用， 体内平衡，并确定由金属离子限制和 中毒这项工作将建立在我们最近确定的主要外排系统的铁 和锰。从这些研究的见解将直接相关的类似压力 人类病原体中存在的反应。免疫系统也限制病原体的生长 通过产生抗菌肽和溶解酶，这两者都影响细胞的完整性 信封.细胞被膜也是我们许多最重要的抗生素的靶点。在第二 项目，我们已经定义了几个不同的细胞包膜应力反应在B。subtilis，重点是 由其他sigma因子调节的那些。我们发现了一系列突变体， 应激反应途径和对细胞敏感性提高关键中枢代谢途径 壁抗生素，包括至关重要的β-内酰胺。此外，我们还探索了新的 发现了抗生素协同作用，可能对临床方法产生影响。选择 抗生素耐药抑制因子为阐明抗生素耐药的基础提供了一种强有力的方法。 协同作用，以及特定应激反应途径的作用。这些通路是细胞 通常，除了它们在感测和响应抗生素- 诱导的压力，并牵连在抗生素耐受性和耐药性的出现， 病原体