Marie Skłodowska-Curie Action EF - DRIPBEAT

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Introduction

Marie Skłodowska-Curie Action “Drug repurposing for inhibiting pathogenic biofilms and potentiating the activity of antibiotics” (DRIPBEAT) is an Individual Fellowship (European Standard) project that will focus on the development of novel anti-biofilm strategies for potentiating the efficacy of conventional antibiotics and improving the treatment outcomes of chronic infections, especially in cystic fibrosis patients. This project utilizes multidisciplinary approaches including medical microbiology, structural biology and computational pharmacology, bringing together experts from different fields. Moreover, the results obtained from this project may also attract industrial partners for exploition, which will significantly enhance its translational impact. The fellowship is granted to Dr. Yuming Cai under the supervision of Prof. Tom Coenye and Prof. Aurélie Crabbé (Ghent University, Belgium), and will run from December 2021 until November 2023.

Project description

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.

Objectives

DRIPBEAT will train Dr. Yuming Cai to:

  • identify key genes that regulate the formation of biofilms/aggregates grown in synthetic sputum among different CF clinical isolates
  • predict the protein structures of selected genes and screen for optimal drugs that modulate the activities of these proteins in silico
  • test candidate drugs on biofilms grown in human cells and mice, with and without conventional antibiotics

Role of Ghent University

Ghent University hosts and trains the fellow. It provides an excellent institutional environment that supports innovation and collaborative research, and offers a range of personalized career path coaching to the fellow, which will enhance her skills and competitiveness in future academic job.

Website

https://www.ugent.be/fw/pharmaceutical-analysis/en/research/micro

Contact

Prof. Dr. Tom Coenye
Laboratory of Pharmaceutical Microbiology
+32 (0)9 264 81 41
e-mail