Pseudomonas quinolone signal and two-component systems; Unravelling the intricate network of gene regulation in Pseudomonas aeruginosa

假单胞菌喹诺酮信号和双组分系统；

• 批准号: BB/K003348/1
• 负责人: Alan Brown
• 金额: $ 44.52万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK003348%2F1
• 关键词: Pseudomonas; quinolone; signal; two; component

P. aeruginosa causes around 10% of all healthcare-associated infections in the UK and is a significant cause of mortality. The organism's intrinsic and acquired antibiotic resistance hinders effective treatment, with multi-drug resistance (MDR) frequently observed. This MDR has increased reliance on the antibiotic colistin, which is frequently considered as a drug of last resort for the treatment of infections caused by MDR bacteria. However, as a result of the increasing reliance on colistin, colistin resistance is increasingly reported, with resistance rates as high as 40%. Colistin resistance in P. aeruginosa is typically mediated by alterations to the bacterial surface that reduce binding of the colistin antibiotic. These surface modifications are normally tightly controlled by regulatory systems within the bacterial cell termed two-component systems (TCSs). However, colistin-resistant P. aeruginosa typically possess mutations within these TCSs that result in their permanent activation, causing the surface modifications to be present all the time. Work underway within our laboratories is investigating the wider significance of these TCS mutations. Unexpectedly, we have found that the permanent activation of these TCSs enhances the activity of another distinct gene regulatory network, termed the PQS quorum sensing system. We believe that the same surface modifications that are switched on by the TCSs to confer colistin resistance are also responsible for enhancing PQS activity. The PQS quorum sensing system is an important regulator of virulence (the ability to cause disease) in P. aeruginosa. Consequently, colistin resistance conferred by permanent TCS activation will impact on the infection process through the action of PQS. These observations provide completely new insight into the interplay between gene regulatory networks in P. aeruginosa, and how they control virulence. The proposed research aims to define the precise mechanism by which TCS activation results in enhanced activity of the PQS quorum sensing system. We will employ a variety of methods to assess this interaction at every step of the pathway, including how the TCSs themselves are activated, which surface modifications occur as a consequence, and how those surface modifications impact on the activity of the PQS system. The overall aim of the research is to assess the extent to which the PQS system is responsible for conferring the multitude of effects previously attributed to the TCSs. These studies will give unique insight into several aspects of the P. aeruginosa biology, thus significantly advancing the scientific field. Long-term, there are potential applications and patient benefit that might be enabled by this research as both TCSs and quorum sensing are widely recognised as novel therapeutic targets for new antibiotics. By defining the nature of the linkage of these two regulatory systems, the proposed studies may promote the rational design of new antimicrobials that target these systems in combination. Given the lack of new antibiotics being developed that possess significant activity against bacteria such as P. aeruginosa, new antimicrobial strategies are urgently required in order to lessen the burden of infectious diseases on society. In addition, by highlighting the unintended consequences of colistin resistance, these studies may be used to guide antibiotic prescribing practices in the future, with a view to improving patient management.

在英国，铜绿假单胞菌引起约10%的医疗保健相关感染，是死亡的重要原因。生物体的内在和获得性抗生素耐药性阻碍了有效的治疗，经常观察到多药耐药性（MDR）。这种MDR增加了对抗生素粘菌素的依赖，粘菌素通常被认为是治疗MDR细菌引起的感染的最后药物。然而，由于对粘菌素的依赖性增加，粘菌素耐药的报道越来越多，耐药率高达40%。铜绿假单胞菌中的粘菌素抗性通常由细菌表面的改变介导，所述改变减少了粘菌素抗生素的结合。这些表面修饰通常受到细菌细胞内称为双组分系统（TCS）的调节系统的严格控制。然而，粘菌素耐药铜绿假单胞菌通常在这些TCS中具有突变，导致其永久活化，导致表面修饰一直存在。我们的实验室正在研究这些TCS突变的更广泛意义。出乎意料的是，我们发现这些TCS的永久激活增强了另一个独特的基因调控网络的活性，称为PQS群体感应系统。我们认为，由TCS开启以赋予粘菌素抗性的相同表面修饰也负责增强PQS活性。PQS群体感应系统是铜绿假单胞菌毒力（致病能力）的重要调节因子。因此，TCS永久激活所产生的粘菌素耐药性将通过PQS的作用影响感染过程。这些观察结果为铜绿假单胞菌基因调控网络之间的相互作用以及它们如何控制毒力提供了全新的见解。该研究旨在确定TCS激活导致PQS群体感应系统活性增强的确切机制。我们将采用各种方法来评估这种相互作用在每一步的途径，包括如何TCS本身被激活，表面修饰发生的结果，以及这些表面修饰如何影响PQS系统的活性。研究的总体目标是评估PQS系统在多大程度上负责赋予以前归因于TCS的多种效应。这些研究将为铜绿假单胞菌生物学的几个方面提供独特的见解，从而显着推进科学领域。从长远来看，这项研究可能会带来潜在的应用和患者利益，因为TCS和群体感应被广泛认为是新抗生素的新治疗靶点。通过定义这两个调节系统的联系的性质，拟议的研究可能会促进针对这些系统组合的新抗菌剂的合理设计。鉴于缺乏正在开发的对细菌如铜绿假单胞菌具有显著活性的新抗生素，迫切需要新的抗微生物策略以减轻传染病对社会的负担。此外，通过强调粘菌素耐药性的非预期后果，这些研究可用于指导未来的抗生素处方实践，以改善患者管理。