Molecular Biofilm Biology

Biofilm formation mechanisms

Biofilms are communities of aggregated bacterial cells embedded in an extracellular polymeric matrix, and they are associated with numerous chronic infections since bacteria in biofilms are tolerant to antimicrobial treatments and host immune defenses. Current research suggests that the molecule c-di-GMP constitutes a ubiquitous intracellular regulator of bacterial biofilm formation. High levels of c-di-GMP induce formation of biofilms, whereas low levels of c-di-GMP induce a planktonic bacterial lifestyle. The level of c-di-GMP in bacteria is determined by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) which contain catalytic GGDEF and EAL/HD-GYP domains as well as regulatory domains. The research project is aimed at obtaining knowledge of the regulation of the activity of DGCs and PDEs, as well as on identification of down-stream c-di-GMP affecter proteins. This knowledge may reveal novel molecular targets for new drugs that can prevent or cure biofilm infections.

Funding: The European Research Council and The Novo Nordisk Foundation

Mechanisms of biofilm-associated antimicrobial tolerance

It is well established that bacterial biofilms are more tolerant to antibiotics than planktonic bacteria. Several factors are known to play a role in the high antimicrobial tolerance displayed by biofilms, including restricted antibiotic penetration, physiological heterogeneity, and induction of specific antibiotic resistance genes. However, our current knowledge is fragmented and the relative importance of the different factors is not known. Accordingly, more knowledge is warranted about antibiotic tolerance mechanisms in order for us to develop effective treatments against biofilm infections. In a collaboration with Professor Leo Eberl at the University of Zürich, we use the next-generation DNA sequencing technique Tn-Seq to identify genes that play a role in antibiotic tolerance of Pseudomonas aeruginosa and Burkholderia cenecepacia biofilms. Thereby, the proteins and molecular mechanisms underlying antibiotic tolerance can be identified, and new drug targets can be suggested.

Funding: Independent Research Fund Denmark and The Novo Nordisk Foundation

Development of anti-biofilm compounds

Biofilms formed by opportunistic pathogenic bacteria can resist antimicrobial therapy, and therefore cause considerable problems in medical settings. However, if forced away from the protective biofilm-state to a free-living planktonic mode, the bacteria become susceptible to antimicrobials. Current research indicates that the secondary messenger c-di-GMP is a general controller of the biofilm lifestyle in bacteria. High internal levels of c-di-GMP induce production of extracellular matrix components which promote biofilm formation, whereas low c-di-GMP levels down-regulate the production of extracellular matrix components and lead bacteria to the planktonic mode of life. We use a combined in silico docking and high-throughput screening approach for the identification of compounds that can activate or inhibit selected PDEs and DGCs. Such compounds are expected to serve as lead molecules for the development of drugs that can cure problematic bacterial infections.

Funding: Independent Research Fund Denmark and The Novo Nordisk Foundation

Chemical compounds that impede the pathogenic effects of Staphylococcus aureus in atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease that affects up to 5% of adults and 20% of children worldwide. The skin of individuals with AD is often colonized with Staphylococcus aureus, and this bacterium exacerbates the disease due to its production of toxins that induce inflammation. A healthy skin microbiota can to some extent suppress AD symptoms, and therefore antibiotic treatment is not recommended for treatment of AD. More rational strategies aim at inhibiting the production of toxins in S. aureus. The aim of the research project is to develop chemical compounds that inhibit the production of toxins in S. aureus, and impede the pathogenic effects of S. aureus in atopic dermatitis, without disturbing the beneficial commensal skin bacteria. 

Funding: The LEO Foundation and Sygeforsikringen danmark Sundhedsdonationer

Independent Research Fund Denmark

European Commission – Horizon-MSCA

The LEO Foundation

Novo Nordisk Foundation  - Project Grants in Bioscience and Basic Biomedicine

Novo Nordisk Foundation  - Infectious Diseases Catalyst Grants

Novo Nordisk Foundation - Exploratory Interdisciplinary Synergy Programme

Sygeforsikringen danmark Sundhedsdonationer

Lundbeck Foundation

Carlsberg Foundation

Kirsten og Freddy Johansens Fond

Hørslev Fonden

Oda og Hans Svenningsens Fond