Recent years have witnessed rapid progress in our understanding of the biofilm life cycle in several bacterial pathogens. Distinct stages and traits that appear to reflect commonalities in biofilm biology, across species, as well as potentially being specific for a given pathogenic organism are now being deciphered. SCELSE is taking a conceptually different approach to antimicrobial research with the merger of biofilm life cycle biology with its chemistry/chemical biology platform and in vivo biofilm models. The now emerging advances in establishing experimental biofilm community systems enable this shift in antimicrobial research to include community rather than single species based targets. This approach is essential for future antimicrobial drug development, and is reflected by the emerging uptake by the pharmaceutical industry.
SCELSE’s Antibiofilm Drugs integrated programme involves identifying compounds that specifically report on biofilms and the biofilm mode of life, together with developing anti-biofilm drugs to interfere with stages unique to and essential for biofilm development and maintenance. The rationale behind this effort is the now accepted realisation that tomorrow’s antimicrobials and antibiotics must be effective against cells in the biofilm mode, which are many fold more resistant than planktonic cells, and cannot be based on the current mode of action as biocidals.
This integrated program establishes and utilises unique biofilm traits in populations and communities and employs the molecular design of reporter systems, computational and synthetic chemistry, and transcriptomics, as well as and in vivo animal models for testing and validation.
More specifically, SCELSE’s research involves defining targets representing responses or structural features that are key for the biofilm biology. A range of reporter assays has been developed both virtually (in silico) and experimentally, targetting different regulatory levels of quorum sensing, c-di-GMP and nitric oxide intracellular signaling systems, matrix polymers, and secretory/export sites, all of which have delivered leads in library screens. Once identified, antibiofilm agents are tested in concert with antibiotics as tools to combat chronic infections. The programme also involves developing a sophisticated strategy for delivery of such drugs to target sites within the biofilm by creating double (or multiple) warhead compounds that release dispersal agents upon contact with a biofilm target, thus forcing the cells into a more susceptible planktonic state and improving antimicrobial/host immune system efficacy.
Specific research objectives include:
- Identifying response targets/structural features that are key for the biofilm biology;
- Examining anti-biofilm agents in concert with antibiotics as tools to combat chronic infections;
- Creating compounds for biofilm specific release of dispersal agents to provide antimicrobial efficacy against dispersed planktonic cells;
- Identifying drugs that target biofilm mediated infections based on interactions with the host immune system;
- Exploiting the properties of growth cycles under stress conditions as a base for antimicrobial discoveries.