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.

项目概要/摘要细菌和人类有着复杂的关系：我们丰富的共生生物提供带来许多好处，而致病菌则造成巨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、和吞噬细胞。潜在的病原体通过激活特定的适应性来应对这些威胁反应，其中许多对于毒力至关重要。我们研究枯草芽孢杆菌模型的应激反应革兰氏阳性细菌。一个项目致力于应对必需营养素的供应变化金属离子锌、铁和锰。免疫系统通过金属限制病原体的生长隔离，在组织中（例如通过钙卫蛋白）和吞噬作用后。此外，吞噬细胞还会杀死金属中毒细胞。我们已经证明金属离子稳态依赖于特定的金属传感对铁（Fur 和 PerR）、锰（MntR）和锌的限制和过量做出反应的转录因子（Zur 和 CzrA）。我们将描述这些转录因子调控的基因及其在金属中的作用体内平衡，并确定金属离子限制和中毒引起的生理效应。这项工作将建立在我们最近确定的铁和锰的主要流出系统的基础上。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。细胞膜也是一个目标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细胞包膜枯草芽孢杆菌的应激反应，重点关注受替代西格玛因子调节的应激反应。我们已经确定一系列应激反应途径和关键中央代谢途径发生改变的突变体对细胞壁抗生素（包括极其重要的β-内酰胺类）的敏感性较高。此外，我们探索新发现的抗生素协同作用及其对临床方法的可能影响。选择抗生素耐药性抑制因子提供了一种强有力的方法来描述抗生素协同作用的基础，以及特定应激反应途径的作用。这些途径对于细胞包膜稳态至关重要一般来说，除了它们在感知和响应抗生素引起的压力方面的作用外，还涉及病原体出现抗生素耐受性和耐药性。

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