The development of a novel anti-virulence therapeutic against Pseudomonas aeruginosa infection using in vivo and in vitro models.

囊性纤维化(CF)和非囊性纤维支气管扩张症患者的慢性肺部感染使人虚弱，导致进行性和广泛的肺损伤，最终可能导致患者死亡。到成年时，高达80%的患者感染铜绿假单胞菌(PA)。PA最近被世卫组织列为一种关键的人类病原体，迫切需要新的抗生素。这一需求正在推动新的治疗策略的发展，包括抗毒力策略。通常，这些疗法可以用来增强现有抗生素的作用(抗生素管理)，减少细菌病原体。学生将是利物浦大学的研究人员和工业合作伙伴Neem Biotech之间的合作。NXAS401最初来自ajoene(一种从大蒜中提取的大蒜素的热重排得到的活性化合物)，已在人工痰模型中被证明具有群体感应抑制活性，并与妥布霉素联合使用在体内增强细菌清除(未发表初步数据)。在这个项目中，我们将检验NXAS401及其衍生物可以作为一种新的治疗药物与一系列临床相关的抗生素一起用于减轻呼吸道中PA的负担的假设。我们将通过三个目标来实现这一目标：1.在体外人工痰模型和体内小鼠模型(一级和二级主管)中，探讨阿霍烯(NXAS401)与其他抗生素(如粘菌素和妥布霉素、氨曲南赖氨酸和环丙沙星)的潜在协同效应。创建NXAS401衍生物，并表征NXAS401修饰对PA毒力和抗菌治疗的影响(主要和次要主管与工业合作伙伴合作)。开发一种体内高分辨率成像系统，以研究阿霍烯(及其衍生物)对呼吸道细菌的作用动力学(初级和二级主管)。该项目将提供广泛的PA生物学和微生物分子遗传学方面的培训(由一级主管支持)，以及体内模型培训和宿主对治疗的免疫反应(由二级主管支持)。此外，将通过使用IVIS成像系统(由利物浦大学生物外科和成像单位支持)采用跨学科的方法。这将通过开发一种治疗方法来解决，这种疗法可以与一系列抗生素一起使用，这取决于感染PA的菌株和每个患者对特定抗生素的耐受性。新的治疗方法，特别是在抗毒力战略方面，需要开发新的管道来测试有效性。学生身份将加速开发一种新的治疗方法临床试验，并为测试针对PA和其他呼吸道病原体的治疗方法提供一个成熟的平台。

Chronic lung infections in people with cystic fibrosis (CF) and non-CF bronchiectasis are debilitating, cause progressive and extensive lung damage and eventually can lead to patient death. By adulthood up to 80% of patients are infected with Pseudomonas aeruginosa (Pa). Pa has recently been named by WHO as a key human pathogen for which there is an urgent need for new antibiotics. This need is driving the development of novel therapeutics strategies including anti-virulence strategies. Often, these therapeutics can be used to enhance the action of existing antibiotics (antibiotic stewardship) and reduce bacterial pathogenesis.The studentship would be a collaboration between researchers at the University of Liverpool and industrial partner, Neem Biotech. NXAS401, originally derived from Ajoene (an active compound derived from a thermal rearrangement of allicin which is extracted from garlic) has been shown to have quorum sensing inhibition activity in vitro in an artificial sputum model and enhances bacterial clearance in vivo in combination with Tobramycin (unpublished preliminary data). In this project we will test the hypothesis that NXAS401 and derivatives could be used as a novel therapeutic in conjunction with a range of clinically relevant antibiotics to reduce the burden of Pa in the respiratory tract. We will achieve this through three aims:1. To explore the potential synergistic effects of Ajoene (NXAS401) with other antibiotics (such as Colistin and Tobramycin, Aztreonam lysine and Ciprofloxacin) in an in vitro artificial sputum model and an in vivo mouse model (primary and secondary supervisor).2. To create NXAS401 derivatives and characterise the impact of NXAS401 modification on Pa virulence and antimicrobial treatment (primary and secondary supervisor in conjunction with industrial partner).3. To develop a high resolution imaging system in vivo to study the dynamics of Ajoene (and derivatives) action against bacteria in the respiratory tract (primary and secondary supervisor).This project would provide extensive training in Pa biology and microbial molecular genetics (supported by the primary supervisor) and in vivo model training and host immune responses to treatment (supported by the secondary supervisor). In addition, there will be an interdisciplinary approach through the use of the IVIS imaging system (supported by the Biosurgical and Imaging Units, University of Liverpool).CF is a condition that requires the ultimate personalized medicine. This would be addressed by developing a therapeutic that could be used in conjunction with a range of antibiotics depending on the strain of infecting Pa and the tolerability of each patient to particular antibiotics. Novel therapeutics, particularly with regards to anti-virulence strategies, requires the development of new pipelines in which to test effectiveness. The studentship would provide an accelerated leap in developing a novel therapeutic towards clinical trial and an established platform for testing out therapeutics against Pa and other respiratory pathogens.