Bacillus subtilis stress responses

枯草芽孢杆菌应激反应

基本信息

批准号：
10796245
负责人：
John D Helmann
金额：
$ 8.88万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要/摘要细菌和人类具有复杂的关系：我们丰富的共生生物提供许多好处，而致病细菌会造成很大的发病率和死亡率负担。这免疫系统通过营养免疫，抗菌肽，裂解酶，限制细菌生长和吞噬细胞。潜在的病原体通过激活特定的自适应来应对这些威胁反应，其中许多对毒力至关重要。我们研究枯草芽孢杆菌中的压力反应，一个模型克阳性细菌。一个项目解决了对基本养分的不断变化的反应金属离子锌，铁和锰。免疫系统限制了金属病原体的生长隔离，包括在组织中（例如，钙染色素）和吞噬作用后。另外，吞噬细胞杀死通过金属中毒。我们已经证明了金属离子稳态依赖于特定的金属感应响应限制和过量铁（皮草和perr），锰（MNTR）和锌的转录因子（Zur和Czra）。我们将表征由这些转录因子调节的基因，它们在金属中的作用稳态，并确定金属离子限制和中毒所带来的生理影响。这项工作将基于我们最近对铁和锰的主要外排系统的识别。这这些研究的见解将与人类中存在的类似压力反应直接相关病原体。免疫系统还通过产生抗菌肽来限制病原体的生长和裂解酶，两者都会影响细胞包膜的完整性。细胞信封也是我们许多最重要的抗生素。在第二个项目中，我们定义了几个不同的小区信封枯草芽孢杆菌的应力反应，重点是由替代西格玛因子调节的压力反应。我们已经确定了一系列突变体有压力反应途径和关键中央代谢途径的变化的突变体对细胞壁抗生素的敏感性升高，包括至关重要的β-内酰胺。另外，我们探索新发现的抗生素协同作用，可能对临床方法产生影响。选择抗生素抗性抑制剂为描述抗生素协同作用的基础提供了强大的方法，以及特定应力反应途径的作用。这些途径是细胞包膜稳态的核心通常，除了它们在传感和应对抗生素引起的压力方面的作用外，还与病原体中抗生素耐受性和耐药性的出现。

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of extracytoplasmic function (ECF) sigma factor promoter selectivity by spacer region sequence.

DOI：
10.1093/nar/gkx953
发表时间：
2018-01-09
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Gaballa A;Guariglia-Oropeza V;Dürr F;Butcher BG;Chen AY;Chandrangsu P;Helmann JD
通讯作者：
Helmann JD

The Bacillus subtilis monothiol bacilliredoxin BrxC (YtxJ) and the Bdr (YpdA) disulfide reductase reduce S-bacillithiolated proteins.

DOI：
10.1016/j.redox.2021.101935
发表时间：
2021-06
期刊：
Redox biology
影响因子：
11.4
作者：
Gaballa A;Su TT;Helmann JD
通讯作者：
Helmann JD

A Central Role for Magnesium Homeostasis during Adaptation to Osmotic Stress.

DOI：
10.1128/mbio.00092-22
发表时间：
2022-02-22
期刊：
mBio
影响因子：
6.4
作者：
Wendel BM;Pi H;Krüger L;Herzberg C;Stülke J;Helmann JD
通讯作者：
Helmann JD

Antagonism of Two Plant-Growth Promoting Bacillus velezensis Isolates Against Ralstonia solanacearum and Fusarium oxysporum.

两种促进植物生长的贝莱斯芽孢杆菌分离株对青枯雷尔斯顿菌和尖孢镰刀菌的拮抗作用

DOI：
10.1038/s41598-018-22782-z
发表时间：
2018-03-12
期刊：
Scientific reports
影响因子：
4.6
作者：
Cao Y;Pi H;Chandrangsu P;Li Y;Wang Y;Zhou H;Xiong H;Helmann JD;Cai Y
通讯作者：
Cai Y

A model industrial workhorse: Bacillus subtilis strain 168 and its genome after a quarter of a century.

DOI：
10.1111/1751-7915.14257
发表时间：
2023-06
期刊：
MICROBIAL BIOTECHNOLOGY
影响因子：
5.7
作者：
Bremer, Erhard;Calteau, Alexandra;Danchin, Antoine;Harwood, Colin;Helmann, John D.;Medigue, Claudine;Palsson, Bernhard O.;Sekowska, Agnieszka;Vallenet, David;Zuniga, Abril;Zuniga, Cristal
通讯作者：
Zuniga, Cristal