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Mechanisms of cellular respiration-dependent cell lysis and its impact on biofilm formation and disassembly in Staphylococcus aureus.

细胞呼吸依赖性细胞裂解机制及其对金黄色葡萄球菌生物膜形成和分解的影响。

基本信息

批准号：
10412146
负责人：
Jeff M Boyd
金额：
$ 37.68万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

项目摘要

The objectives of this proposal are to determine a) the factors and mechanisms that modulate biofilm formation and dispersal as a function of cellular respiration in Staphylococcus aureus, b) determine how the expression of these factors is regulated, and c) determine the molecular stimuli for a regulatory system that responds to alterations in the cellular respiratory status. Staphylococcus aureus is a human commensal and a leading cause of hospital and community acquired infections. For S. aureus to colonize and invade host tissues, it must successfully sense and respond to environmental perturbations and transition between individualistic and multicellular behaviors. S. aureus has the ability to form multicellular communities called biofilms, which are the etiologic agents of recurrent staphylococcal infections. We have found that S. aureus modulates biofilm formation as a function of electron flux though respiratory pathways. We have found that when S. aureus is growing without a terminal electron acceptor (fermentative growth) there is an increase in cell lysis, which leads to the release of intracellular components including DNA. The DNA that is released is vital to biofilm integrity where it aids in holding the cells together in the biofilm matrix. We also discovered that the addition of a terminal electron acceptor to fermentative biofilms resulted in biofilm dispersal. We have identified two global regulatory systems that mediate fermentative biofilm formation. Both of these regulatory systems have been shown to be necessary for pathogenesis, but their molecular stimuli are currently unknown. The overarching goal of this project is to understand the physiological changes that occur within S. aureus upon changes in cellular respiration, and examine how these changes affect the community structure. We will use genetic, physiologic, biochemical, and molecular techniques to investigate an understudied variable that causes S. aureus to modulate cell lysis, and thereby affect biofilm formation and biofilm dispersal. We will further define the factors involved in fermentative cell lysis and biofilm formation. We will also define the factors and molecular mechanisms involved in the dispersal of fermentative biofilms. We will examine the molecular stimuli of one regulatory system (Sae) and examine how another regulatory system (Srr) controls the expression of factors that alter cell lysis and biofilm formation. Ultimately, we would like to apply our findings to modulate the behavior of S. aureus using molecules that alter cell signaling, and thereby, positively affect infection outcomes. Completion of the studies will help provide knowledge about two requirements for staphylococcal pathogenesis: environmental sensing and biofilm formation.

本提案的目的是确定a）调节生物膜形成的因素和机制和扩散作为金黄色葡萄球菌中细胞呼吸的函数，B）确定表达如何 c）确定对这些因子中的一个进行调节的调节系统的分子刺激物，细胞呼吸状态的改变。金黄色葡萄球菌是一种人类病原体，医院和社区获得性感染。对于鼠伤寒沙门氏金黄色葡萄球菌定殖和侵入宿主组织，它必须成功地感知和应对环境干扰以及个人主义和多细胞行为S.金黄色葡萄球菌具有形成称为生物膜的多细胞群落的能力，复发性葡萄球菌感染的病原体。我们发现S.金黄色葡萄球菌调节生物膜形成作为通过呼吸途径的电子通量的函数。我们发现当S.金黄色在没有末端电子受体的情况下生长（发酵生长），细胞裂解增加，导致细胞内成分包括DNA的释放。释放的DNA对生物膜至关重要完整性，其中其有助于将细胞一起保持在生物膜基质中。我们还发现，发酵生物膜的末端电子受体导致生物膜分散。我们已经确定了两个全球性的调节系统介导发酵生物膜形成。这两个监管体系都是被证明是必要的发病机制，但他们的分子刺激是目前未知的。总体本项目的目的是了解S.金黄色葡萄球菌细胞呼吸，并研究这些变化如何影响社区结构。我们将使用基因，生理，生化和分子技术来调查一个未充分研究的变量，导致S。金黄色葡萄球菌，以调节细胞裂解，从而影响生物膜形成和生物膜分散。我们将进一步定义参与发酵细胞裂解和生物膜形成的因素。我们还将定义这些因素，发酵生物膜分散的分子机制。我们将检查分子刺激一个调节系统（Sae）的表达，并检查另一个调节系统（Srr）如何控制改变细胞溶解和生物膜形成的因素。最终，我们希望将我们的发现应用于调节 S的行为。金黄色葡萄球菌使用改变细胞信号传导的分子，从而积极影响感染结果。研究的完成将有助于提供关于葡萄球菌感染的两个要求的知识。发病机制：环境感知和生物膜形成。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contribution of YjbIH to Virulence Factor Expression and Host Colonization in Staphylococcus aureus

DOI：
10.1128/iai.00155-19
发表时间：
2019-06-01
期刊：
INFECTION AND IMMUNITY
影响因子：
3.1
作者：
Austin, Crystal M.;Garabaglu, Siamak;Bose, Jeffrey L.
通讯作者：
Bose, Jeffrey L.

Bayesian Modeling and Intrabacterial Drug Metabolism Applied to Drug-Resistant Staphylococcus aureus.

DOI：
10.1021/acsinfecdis.1c00265
发表时间：
2021-08-13
期刊：
ACS infectious diseases
影响因子：
5.3
作者：
Patel JS;Norambuena J;Al-Tameemi H;Ahn YM;Perryman AL;Wang X;Daher SS;Occi J;Russo R;Park S;Zimmerman M;Ho HP;Perlin DS;Dartois V;Ekins S;Kumar P;Connell N;Boyd JM;Freundlich JS
通讯作者：
Freundlich JS

Synthesis, Characterization, and Antimicrobial Investigation of a Novel Chlorhexidine Cyclamate Complex.

DOI：
10.1021/acs.cgd.0c00107
发表时间：
2020-08-05
期刊：
Crystal growth & design
影响因子：
3.8
作者：
Dubovoy V;Desai P;Hao Z;Cheng CY;Verma G;Wojtas L;Brinzari TV;Boyd JM;Ma S;Asefa T;Pan L
通讯作者：
Pan L

Staphylococcus aureus lacking a functional MntABC manganese import system has increased resistance to copper.