Dissecting the mechanism and regulation of bacterial secreted peptidases and their role in biofilms
剖析细菌分泌肽酶的机制和调节及其在生物膜中的作用
基本信息
- 批准号:BB/Y005333/1
- 负责人:
- 金额:$ 61.24万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2024
- 资助国家:英国
- 起止时间:2024 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Bacterial communities often organise in structures called biofilms. These communities are associated with a self-produced matrix containing extracellular DNA, RNA, proteins and complex sugars. Biofilms are resilient to environmental stressors including nutrient fluctuation, antibiotic treatment, and changes in temperature. Biofilm resilience is vital to the bacterial collective but presents a colossal economic and health challenge as bacteria in these populations are difficult to eradicate. Up to 4 out of 5 of all bacterial cells in the planet are associated in biofilms. A report by the NIH indicates that over 80% of microbial infections in the human body are caused by biofilms, many of which are resistant to standard antibiotics. Pseudomonas aeruginosa is a model organism to understand biofilm development and its role in survival and recalcitrance to antibiotic treatment. It can also lead to serious infections specially in immunocompromised patients. No drug currently in the market specifically targets bacterial biofilms. All drugs currently in the market target actively dividing bacteria, and therefore are not as efficient eradicating slow growing bacteria, which is often the state encountered in biofilms. Extracellular enzymes that can degrade proteins and peptides are important components of biofilms. These enzymes are crucial for nutrient scavenging and to shape the structure of biofilms, in a process called remodelling, which is essential for biofilm survival and propagation. Extracellular enzymes are very attractive targets as antimicrobials do not need to enter cells and can be embedded in dressings and topic gels. The Czekster lab have demonstrated proof of principle that targeting an important extracellular component of the bacterial matrix leads to bacterial cell death in biofilms formed by the Pseudomonas aeruginosa. This work demonstrated the feasibility of exploiting the mechanism by which the activity of extracellular peptidases is regulated to design specific inhibitors, which lead to cell death in a biofilm. It also highlighted many unanswered questions in biofilm biology, regulation and survival. It set the stage to the project proposed here. This project will address outstanding questions in biofilm biology and enzymology, dissecting the mechanism and role that extracellular peptidases play in protein and peptide turnover in biofilm communities. We will determine whether a conserved element of these extracellular peptidases, the protein associated domain, can be exploited to target peptidases from other microbes. We will also determine the precise mechanism by which Pseudomonas aeruginosa are dying due to the peptidase inhibition. We will employ enzymology, inhibitor design and characterisation, microbiology, proteomics and metabolomics, in a tailored interdisciplinary programme to unveil novel strategies and compounds to specifically target bacterial biofilms.
细菌群落通常组织在称为生物膜的结构中。这些群落与含有细胞外DNA、RNA、蛋白质和复合糖的自产基质相关。生物膜对环境压力源具有弹性,包括营养波动,抗生素治疗和温度变化。生物膜的弹性对细菌群体至关重要,但由于这些群体中的细菌难以根除,因此带来了巨大的经济和健康挑战。地球上所有细菌细胞中有五分之四与生物膜有关。美国国立卫生研究院的一份报告表明,人体内超过80%的微生物感染是由生物膜引起的,其中许多对标准抗生素具有耐药性。铜绿假单胞菌是了解生物膜发展及其在生存和抗生素治疗耐受性中的作用的模式生物。它还可能导致严重的感染,特别是在免疫功能低下的患者中。目前市场上没有药物专门针对细菌生物膜。目前市场上的所有药物都是针对活跃分裂的细菌,因此不能有效地根除缓慢生长的细菌,这通常是生物膜中遇到的状态。胞外酶是生物膜的重要组成部分,能降解蛋白质和多肽。这些酶对于养分清除和塑造生物膜的结构至关重要,在一个称为重塑的过程中,这对生物膜的生存和繁殖至关重要。胞外酶是非常有吸引力的靶标,因为抗菌剂不需要进入细胞,并且可以嵌入敷料和局部凝胶中。Czekster实验室已经证明了靶向细菌基质的重要细胞外组分导致铜绿假单胞菌形成的生物膜中的细菌细胞死亡的原理。这项工作证明了利用调节细胞外肽酶活性的机制来设计导致生物膜中细胞死亡的特异性抑制剂的可行性。它还强调了生物膜生物学、调节和生存中许多尚未解答的问题。它为这里提出的项目奠定了基础。本项目将解决生物膜生物学和酶学中的突出问题,剖析细胞外肽酶在生物膜群落中蛋白质和肽周转中的机制和作用。我们将确定这些细胞外肽酶的保守元件,蛋白质相关结构域,是否可以被利用来靶向来自其他微生物的肽酶。我们还将确定铜绿假单胞菌由于肽酶抑制而死亡的确切机制。 我们将采用酶学,抑制剂设计和表征,微生物学,蛋白质组学和代谢组学,在一个量身定制的跨学科计划,以揭示新的策略和化合物,专门针对细菌生物膜。
项目成果
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