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CF性支气管扩张患者的慢性肺部感染使人衰弱，引起进行性和广泛的肺损伤，最终可导致患者死亡。到成年时，高达80%的患者感染铜绿假单胞菌（Pa）。最近，世卫组织将疟原虫列为一种重要的人类病原体，迫切需要新的抗生素。这种需求正在推动包括抗毒策略在内的新型治疗策略的发展。通常，这些治疗方法可用于增强现有抗生素的作用（抗生素管理）并减少细菌发病机制。该奖学金将由利物浦大学的研究人员和工业合作伙伴Neem生物技术公司合作设立。NXAS401最初来源于Ajoene（一种从大蒜中提取的大蒜素的热重排活性化合物），已在体外人工痰模型中显示出群体感应抑制活性，并与妥布霉素联合增强体内细菌清除（未发表的初步数据）。在这个项目中，我们将测试NXAS401及其衍生物可以作为一种新的治疗方法与一系列临床相关的抗生素一起使用，以减轻呼吸道中Pa的负担。我们将通过三个目标来实现这一目标。在体外人工痰模型和小鼠体内模型（一级和二级监督）中，探讨阿若尼（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）的潜在协同作用。2 .创建NXAS401衍生物，并描述NXAS401修饰对Pa毒性和抗菌处理的影响（主要和次要主管与工业合作伙伴一起）。开发高分辨率体内成像系统，研究阿若烯（及其衍生物）对呼吸道细菌的作用动力学（主要和次要监督）。该项目将提供广泛的Pa生物学和微生物分子遗传学培训（由第一导师支持），以及体内模型培训和宿主对治疗的免疫反应（由第二导师支持）。此外，通过使用IVIS成像系统（由利物浦大学生物外科和成像单元支持），将采用跨学科方法。CF是一种需要终极个性化医疗的疾病。这将通过开发一种治疗方法来解决，这种治疗方法可以与一系列抗生素结合使用，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，特别是在抗毒策略方面，需要开发新的管道来测试有效性。该奖学金将为开发一种新的临床试验治疗方法提供加速飞跃，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in vitro in an artificial sputum model and enhances bacterial clearance in vivo in combination with Tobramycin (unpublished preliminary data).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.