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

• 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

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个体的皮肤、鼻孔或其他粘膜表面上发现，而不会引起任何症状或伤害。然而，S.金黄色葡萄球菌还可引起从小的皮肤感染到危及生命的侵入性疾病的多种感染。令人震惊的是，许多S。金黄色葡萄球菌菌株已经获得了对多种抗菌剂的抗性，结果是S.金黄色葡萄球菌仍然是世界范围内耐药性医疗保健相关感染的主要原因之一。由此造成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以最终开发新的抗菌剂是有意义的。本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性。这两种酶对S.金黄色。乍一看，它们之间没有明显的联系，因为GlmM是生产必需的细胞壁前体所必需的，DacA负责生产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在某种程度上是相互关联的。因此，DacA和GlmM是协调细胞壁聚合物肽聚糖合成与c-di-AMP调节途径的潜在核心参与者。该项目的目的是提供DacA/GlmM复合物的图像，以准确显示这两种蛋白质如何相互作用，找出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甲氧西林抗性。总之，这项工作将产生关于两种重要细菌酶的相互依赖性的有价值的信息，这两种酶将革兰氏阳性细菌病原体S.金黄色。由于S.金黄色葡萄球菌对人类感染，这项工作的输出对必要的细胞途径可能提供未来的机会，为发展新的治疗方法干扰的增长。金黄色葡萄球菌和潜在的许多其他革兰氏阳性病原体。

项目成果

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.

• DOI: 10.1016/j.mib.2021.01.007
• 发表时间: 2021-04
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Rismondo J;Gillis A;Gründling A
• 通讯作者: Gründling A

GtcA is required for LTA glycosylation in Listeria monocytogenes serovar 1/2a and Bacillus subtilis

单核细胞增生李斯特菌血清型 1/2a 和枯草芽孢杆菌中的 LTA 糖基化需要 GtcA

• DOI: 10.1101/2019.12.12.873851
• 发表时间: 2019
• 作者: Rismondo J

EslB is required for cell wall biosynthesis and modification in Listeria monocytogenes

单核细胞增生李斯特菌的细胞壁生物合成和修饰需要 EslB

• DOI: 10.1101/2020.02.03.932061
• 发表时间: 2020
• 作者: Rismondo J