Biofilm is a growth mode of pathogenic bacteria that are closely associated with chronic infections, leading to much higher tolerance to antibiotics and treatment failures. New adjunctive therapeutic strategies for biofilm disruption are thus urgently required. Cyclic-di-GMP, a small molecule promoting biofilm formation that can be found in most pathogens, is a promising drug target. Whilst this signaling pathway has been extensively studied at molecular levels, only few compounds that reduce c-di-GMP levels and inhibit biofilms were identified in vitro so far. Furthermore, the experimental designs were mainly based on standard strains and medium that are far from recapitulating in vivo situations. As a result, candidate compounds that can be subjected to investigational applications remain scarce.

To increase the chance of searching for optimal c-di-GMP inhibitors, clinical P. aeruginosa strains from CF patients will be cultured in synthetic sputum that better mimics their growth conditions in diseased lungs. Transcriptionally altered genes that modulate c-di-GMP levels and contribute to the biofilm formation will be identified and subjected to protein structural modelling, followed by computational drug screening from commercial database. Candidate drugs will then be tested in vitro, in infected human cells and in animals, thus adding great value to downstream clinical research. With such a comprehensive methodology, this project is not only beneficial for combating chronic infections, but will also equip an early career researcher with different professional skills that significantly enhances her future career prospects.

The fellow will be fully integrated into the Laboratory of Pharmaceutical Microbiology (LPM) at UGent, a leading group in Europe investigating combination therapy against biofilms. During the project, the fellow will make multiple short visits to UAntwerpen, and may potentially interact with some industrial partners. The research outputs include Open Access publications, presentations at international conferences, and potential patents. Furthermore, the fellow will actively participate in different public events, such as “Dag van de Wetenschap”, “Pint of Science” and European Researchers’ Night, to spread the knowledge of biofilms to laypersons.