权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Quorum sensing and virulence in Gram positive pathogens: structure, function and inhibition of the agr system

革兰氏阳性病原体的群体感应和毒力：agr系统的结构、功能和抑制

基本信息

批准号：
MR/N010477/1
负责人：
Paul Williams
金额：
$ 218.55万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN010477%2F1
关键词：
Quorum sensing virulence Gram positive

项目摘要

The emergence, rapid spread and persistence of multi-antibiotic resistant bacteria is considered by the WHO as one of the three greatest global threats to human health. Antimicrobial resistance (AMR) threatens the treatment and outcome of even simple infections and common medical interventions (surgery, dentistry, obstetrics) that until recently were considered low-risk. Against this backdrop, the development of new classes of antibiotics has lagged far behind the urgent requirement for new drugs. This is in part because discovering safe and effective new antibiotics is scientifically challenging and because many major pharmaceutical companies withdrew from developing expensive new drugs likely to become rapidly obsolete through resistance. Consequently, novel antibacterial drugs with that do not succumb to conventional antibiotic resistance mechanisms, nor select for new forms of resistance, nor damage the host microflora, are desperately needed. The discovery of such drugs depends on a thorough understanding of the physiology and molecular biology of pathogenic bacteria and their strategies for colonizing host tissues and combatting host immune defences. These include the deployment of multiple virulence factors such as enzymes and toxins that cause host tissue damage and disease. Conventional antibiotics mostly act by killing bacteria and so exert enormous selective pressures leading to the emergence of resistant strains. If however, instead of killing bacteria, we simply prevent them deploying their virulence factors, infection should be attenuated with less pressure for resistance to emerge. Research on bacterial virulence factors and their control systems enables us to identify molecular target 'weak points' in bacteria so that methods for screening drug-like compounds active against such targets can be designed and new antibacterial drugs discovered. One promising target for anti-virulence agents is quorum sensing (QS). Although bacteria are single cell organisms, they can synchronize the activities of all the cells in a population through cell-to-cell communication. This is achieved through the production and sensing of signal molecules that inform the infecting bacteria that they are present in sufficient numerical strength to deploy their virulence factors and mount an attack. QS systems offer multiple molecular targets for anti-infective agents that include the production, export and response to QS signal molecules. In problematic multi-antibiotic resistant pathogens such as Staphylococcus aureus (including MRSA) and Clostridium difficile, virulence factors including many major exotoxins are controlled by the agr QS system that employs autoinducing peptide signal (AIP) molecules. In this research project we are seeking to understand in depth the way in which S. aureus produces and exports AIP signal molecules via two transmembrane proteins called AgrB and 1984 since these are key to QS and hence virulence. We propose to use a multidisciplinary approach combining microbiology with chemistry, structural biology to elucidate the functions and 3D structures of the key enzymes involved in AIP generation. We also plan to discover how AIPs are exported out of the bacterial cell and to develop new drug-like molecules that block AIP production generation in staphylococci. These will be tested for efficacy alone and in combination with conventional antibiotics in laboratory media and by using novel infection imaging tools that will provide information on when and where agr-dependent QS is switched on or off. The work will focus primarily on S. aureus but promising compounds will also be tested against enterococci, clostridia and listeria and other. other staphylococcal species.

世界卫生组织认为，多重抗生素耐药细菌的出现、快速传播和持续存在是全球对人类健康的三大威胁之一。抗生素耐药性（AMR）甚至威胁到简单感染和常见医疗干预（手术，牙科，产科）的治疗和结果，直到最近才被认为是低风险的。在此背景下，新型抗生素的开发远远落后于对新药的迫切需求。这部分是因为发现安全有效的新抗生素在科学上具有挑战性，而且许多大型制药公司退出了开发昂贵的新药，这些新药可能会因耐药性而迅速过时。因此，迫切需要不屈服于常规抗生素耐药性机制，也不选择新形式的耐药性，也不破坏宿主微生物菌群的新型抗菌药物。这些药物的发现取决于对病原菌的生理学和分子生物学及其在宿主组织中定植和对抗宿主免疫防御的策略的透彻理解。这些包括部署多种毒力因子，如引起宿主组织损伤和疾病的酶和毒素。传统的抗生素主要通过杀死细菌来起作用，因此施加了巨大的选择压力，导致耐药菌株的出现。然而，如果我们不是杀死细菌，而是简单地阻止它们部署它们的毒力因子，那么感染应该会减弱，而产生耐药性的压力也会减少。对细菌毒力因子及其控制系统的研究使我们能够识别细菌中的分子靶标“弱点”，从而可以设计筛选对这些靶标具有活性的药物样化合物的方法，并发现新的抗菌药物。一个有前途的抗病毒剂的目标是群体感应（QS）。虽然细菌是单细胞生物，但它们可以通过细胞间的通讯来同步群体中所有细胞的活动。这是通过产生和感知信号分子来实现的，这些信号分子通知感染细菌它们以足够的数量强度存在，以部署它们的毒力因子并发起攻击。QS系统为抗感染药物提供多个分子靶标，包括QS信号分子的产生、输出和响应。在有问题的多重抗生素耐药病原体如金黄色葡萄球菌（包括MRSA）和艰难梭菌中，包括许多主要外毒素的毒力因子由采用自诱导肽信号（AIP）分子的agr QS系统控制。在这个研究项目中，我们试图深入了解S。金黄色葡萄球菌通过称为AgrB和1984的两种跨膜蛋白产生和输出AIP信号分子，因为这些是QS和毒力的关键。我们建议使用微生物学与化学，结构生物学相结合的多学科方法来阐明参与AIP生成的关键酶的功能和三维结构。我们还计划发现AIP是如何从细菌细胞中输出的，并开发新的药物样分子来阻断葡萄球菌中AIP的产生。将在实验室培养基中单独和与常规抗生素联合使用，并通过使用新型感染成像工具检测这些药物的疗效，这些工具将提供关于何时何地开启或关闭agr依赖性QS的信息。这项工作将主要集中在S。但有前景的化合物也将测试对抗肠球菌、梭菌和沙门氏菌等。其他葡萄球菌物种。

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）

A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin.

DOI：
10.1016/j.chembiol.2022.02.007
发表时间：
2022-07-21
期刊：
CELL CHEMICAL BIOLOGY
影响因子：
8.6
作者：
Murray, Ewan J.;Dubern, Jean-Frederic;Chan, Weng C.;Chhabra, Siri Ram;Williams, Paul
通讯作者：
Williams, Paul

Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

塑造牛体连接的万古霉素二聚体作为抗多药耐药革兰氏阳性细菌的有效抗生素。