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Interaction and interdependency of GlmM and DacA - two essential enzymes required for methicillin resistance in Staphylococcus aureus

GlmM 和 DacA 的相互作用和相互依赖性 - 金黄色葡萄球菌耐甲氧西林所需的两种必需酶

基本信息

批准号：
MR/P011071/1
负责人：
Angelika Grundling
金额：
$ 63.72万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP011071%2F1
关键词：
Interaction interdependency GlmM DacA two

项目摘要

Staphylococcus aureus is frequently found on the skin, nares or other mucosal surfaces of healthy individuals without causing any symptoms or harm. However, S. aureus can also cause a wide variety of infections ranging from small skin infections to life-threatening invasive diseases. Alarmingly, many S. aureus strains have acquired resistance to multiple antimicrobials and as a result S. aureus is still one of the leading causes of antibiotic-resistant healthcare-associated infections worldwide. The resulting difficulty in treating these infections is a major public health concern. Therefore, it is of interest to study biosynthesis pathways and enzymes that are required for bacterial growth to ultimately develop new antimicrobials. The purpose of this study is to characterize the interaction and interdependency of the two staphylococcal enzymes GlmM and DacA. Both enzymes are extremely important for the growth of S. aureus. At the first glance there is no apparent connection between them as GlmM is required for the production of an essential cell wall precursor and DacA is responsible to the production of a recently discovered signalling nucleotide c-di-AMP. However, recent work has indicated that there is a direct protein/protein contact between these two enzymes, suggesting that the pathways that they regulate are somehow interconnected. DacA and GlmM are therefore potentially central players in coordinating the synthesis of the cell wall polymer peptidoglycan with pathways that are regulated by c-di-AMP. The aims of this project are to provide an image of the DacA/GlmM complex in order to show exactly how these two proteins interact, find out how the activity of one enzyme influences the activity of the other and how this interaction affects the growth and methicillin resistance of the cell. In summary, the work will yield valuable information on the interdependency of two important bacterial enzymes, which interconnect two essential cellular processes in the Gram-positive bacterial pathogen S. aureus. Due to the direct link of S. aureus to human infection, the output of this work on essential cellular pathways can potentially offer future opportunities for the development of novel therapeutic approaches interfering with the growth of S. aureus and potentially a number of other Gram-positive pathogens.

金黄色葡萄球菌经常在健康人的皮肤、鼻孔或其他粘膜表面发现，不会造成任何症状或伤害。然而，金黄色葡萄球菌也可以引起各种各样的感染，从轻微的皮肤感染到危及生命的侵袭性疾病。令人担忧的是，许多金黄色葡萄球菌菌株已经对多种抗菌素产生了抗药性，因此金黄色葡萄球菌仍然是全球耐药医疗保健相关感染的主要原因之一。由此带来的治疗这些感染的困难是一个主要的公共卫生问题。因此，研究细菌生长所需的生物合成途径和酶最终开发新的抗菌剂是很有意义的。这项研究的目的是表征两种葡萄球菌酶GlmM和DACA的相互作用和相互依赖。这两种酶对金黄色葡萄球菌的生长都非常重要。乍一看，它们之间没有明显的联系，因为GlmM是产生必要的细胞壁前体所必需的，而DACA负责产生最近发现的信号核苷酸c-di-AMP。然而，最近的研究表明，这两种酶之间存在直接的蛋白质/蛋白质接触，这表明它们调节的途径以某种方式相互联系。因此，DACA和GlmM可能是协调细胞壁聚合物肽聚糖的合成与c-diAMP调节的途径的中心角色。该项目的目的是提供DACA/GlmM复合体的图像，以便准确地显示这两种蛋白质是如何相互作用的，找出其中一种酶的活性如何影响另一种酶的活性，以及这种相互作用如何影响细胞的生长和对甲氧西林的耐药性。总之，这项工作将产生关于两种重要细菌酶的相互依存关系的有价值的信息，这两种酶连接革兰氏阳性细菌病原体金黄色葡萄球菌中的两个基本细胞过程。由于金黄色葡萄球菌与人类感染的直接联系，这项关于基本细胞途径的工作的成果可能为未来开发干扰金黄色葡萄球菌和其他一些革兰氏阳性病原体生长的新的治疗方法提供机会。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EslB Is Required for Cell Wall Biosynthesis and Modification in Listeria monocytogenes.

DOI：
10.1128/jb.00553-20
发表时间：
2021-01-25
期刊：
Journal of bacteriology
影响因子：
3.2
作者：
Rismondo J;Schulz LM;Yacoub M;Wadhawan A;Hoppert M;Dionne MS;Gründling A
通讯作者：
Gründling A

Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.

DOI：
10.1021/acs.jcim.2c00300
发表时间：
2022-05-23
期刊：
JOURNAL OF CHEMICAL INFORMATION AND MODELING
影响因子：
5.6
作者：
Wezen, Xavier Chee;Chandran, Aneesh;Eapen, Rohan Sakariah;Waters, Elaine;Bricio-Moreno, Laura;Tosi, Tommaso;Dolan, Stephen;Millership, Charlotte;Kadioglu, Aras;Grundling, Angelika;Itzhaki, Laura S.;Welch, Martin;Rahman, Taufiq
通讯作者：
Rahman, Taufiq

Modifications of cell wall polymers in Gram-positive bacteria by multi-component transmembrane glycosylation systems.