Drug repurposing for inhibiting pathogenic biofilms and potentiating the activity of antibiotics
Bacterial biofilms are closely associated with chronic infections, leading to much higher tolerance to antibiotics and treatment failures. New strategies for biofilm disruption are thus urgently required. Cyclic-di-GMP, a secondary messenger promoting biofilm formation, is a promising drug target. Only few compounds that reduce c-di-GMP levels and inhibit biofilms were identified so far, and most studies were conducted in vitro using standard medium and reference strains. In this project drugs will be repurposed for targeting c-di-GMP and biofilms to increase the antibiotic susceptibility of clinical Pseudomonas aeruginosa strains. Interdisciplinary approaches will be applied, combining next generation sequencing, gene expression pattern in synthetic sputum, protein structural modelling and computational drug docking, lung epithelial cell infection and murine model. This project will increase the accuracy of drug discovery based on c-di-GMP and significantly expand the skillset of an early career researcher with a strong background in the molecular mechanism of c-di-GMP pathway. The new knowledge in human cell culture and murine model obtained in this fellowship will be crucial for the researcher with a long-term interest in infection treatment. The host laboratory at Ghent University (UGent), a leading group in Europe investigating combination therapy against biofilms, offers an excellent atmosphere fostering both technical and transferable skills. The researcher will also benefit from the supervisor’s extensive research network and the numerous training programs provided by UGent to enhance the future career prospects. The research outputs will provide fresh insights into how genetic and environmental conditions influence c-di-GMP pathway (basic science) and how to select more appropriate compounds for biofilm treatment (applied science), and may also be subjected to clinical trials and attract industrial partners for wider applications.