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

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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in vitro in an artificial sputum model and enhances bacterial clearance in vivo in combination with Tobramycin (unpublished preliminary data).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.