Investigating the metabolic perturbations in host microenvironment induced by antimicrobial peptides during bacterial infection

Pseudomonas aeruginosa is a prominent opportunistic pathogen that can cause chronic lung infections in cystic fibrosis patients, as well as serious acute infections in immunocompromised and injured individuals. However, due to its highly intrinsic and adaptive resistance to a wide range of antibiotics, infections caused by this organism are often very difficult to treat. For this reason, the use of polymyxins (i.e., polymyxin B and colistin) has resurged as a last-line therapeutic option over the last decade. It is known that bacterial response towards polymyxin treatment is sensitive to the surrounding environment; however, how the host immune microenvironment affects the response of P. aeruginosa to polymyxins remains largely unknown. In this project, we will first employ our in vitro host-pathogen-antibiotic (HPA) tripartite model which was well established in our laboratory for another Gram-negative opportunistic pathogen Acinetobacter baumannii to examine the complex molecular interplay from both bacteria and immune cells perspectives, mimicking the physiological infection-treatment condition. Next, we will move further into the in vivo host metabolic microenvironment to establish the in-depth HPA tripartite model in order to precisely investigate how polymyxins perturb host metabolites during P. aeruginosa infection, and how essential metabolites affect polymyxin efficacy and immune function. This project will employ cutting-edge techniques, including quantitative systems pharmacology, stable isotope labelling and MALDI-MS imaging, etc.