Extra-Cytoplasmic Function Sigma Factor Senses and Responds to Beta-Lactam Stress in Gram-Positive Bacteria

项目摘要 治疗细菌感染的抗生素的发现对人类产生了戏剧性和积极的影响 健康。然而，在引入新抗生素后不久，往往会产生抗药性。这个 抗生素耐药细菌的出现和传播被认为是全球卫生紧急情况。在……里面 除了对公众健康的威胁外，抗药性细菌还给 医疗保健系统。很明显，迫切需要针对抗生素耐药性的新方法。这个 细菌的细胞膜是细胞存活所必需的，也是许多最常用的 抗生素包括β-内酰胺类抗生素，如青霉素。这些是普通的广谱抗生素。 通过抑制青霉素结合转肽酶活性靶向肽聚糖的生物合成 蛋白质。我们的长期目标是了解β-内酰胺类药物被革兰素史克感知的机制。 阳性细菌。蜡状芽孢杆菌类中的生物，包括苏云金芽孢杆菌和芽孢杆菌 炭疽菌对β-内酰胺类抗生素高度耐药。这种抵抗力取决于额外的- 细胞质功能σ因子σP，我们已经发现它是由β- 内酰胺类抗生素。ECFσ因子代表了一类重要的信号转导系统 与其他监管制度相比，人们对此了解相对较少。我们发现σP是 在抗σ因子rsiP的蛋白水解性破坏后被激活。我们的数据表明 BT3488是一种青霉素结合蛋白，RsiP的1位裂解需要BT3488。这些发现提出了几个 重要问题：β-内酰胺类抗生素是如何被细胞感知的？以下哪些因素是必需的 激活σP对β-内酰胺类抗生素的反应？在这里，我们建议1)确定BT3488的作用 和rsiP在检测β-内酰胺类药物和控制σP激活方面的作用，以及2)确定所需的其他因素 用于σP的激活。

Project Summary The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However shortly after the introduction of new antibiotics, resistance often develops. The emergence and spread of antibiotic resistant bacteria is considered a worldwide health emergency. In addition to a public health threat, antibiotic resistant bacteria also place a significant financial burden on the health care system. It is clear new methods to target antibiotic resistance are seriously needed. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics including β-lactam antibiotics like penicillin. These are general broad-spectrum antibiotics that target peptidoglycan biosynthesis by inhibiting the transpeptidase activity of penicillin binding proteins. Our long-term goal is to understand the mechanism by which β-lactams are sensed by Gram- positive bacteria. Organisms in the Bacillus cereus group including Bacillus thuringiensis and Bacillus anthracis are highly resistant to β-lactam antibiotics. This resistance is dependent upon the Extra- Cytoplasmic Function (ECF) σ factor σP, which we have found is specifically activated by a subset of β- lactam antibiotics. ECF σ factors represent an important class of signal transduction systems which compared to other regulatory systems are relatively poorly understood. We have found that σP is activated upon the sequential proteolytic destruction of the anti-σ factor RsiP. Our data indicate that BT3488 a penicillin binding protein is required for site-1 cleavage of RsiP. These findings raise several important questions: How are β-lactam antibiotics sensed by the cell? What factors are required for activating σP in response to β-lactam antibiotics? Here we propose to 1) Determine the role of BT3488 and RsiP in sensing β-lactams and controlling σP activation and 2) Identify additional factors required for σP activation.