Ongoing projects in the Michael Givskov Group

Development of a new antimicrobial drug

Most clinically approved antibiotics have been designed based on their ability to kill free-living (planktonic) bacteria. However, in the 21^st century, biofilms considered “the central mode of microbial life”, essential for all life support processes on Earth. This comes with a caveat: bacteria in the biofilm-mode can cause severe AMR infections because this mode limits the healing impact of the prevailing antibiotic-based therapies.

Work on developing an entirely new antibacterial drug paradigm that overcomes AMR was commenced in 2010. Our first drug candidate, named Disperazol, has been designed to target the c-di-GMP governed interconversions between the biofilm mode and the planktonic life-mode of the ESKAPE pathogen Pseudomonas aeruginosa.

Disperazol is the first example of a non-lethal antimicrobial drug, that works by shifting the life-mode of bacteria. Coupling biofilm dismantling with subsequent antibiotic treatment, increases bacterial susceptibility to conventional antibiotics and reduces the overall AMR properties of the infection. c-di-GMP is not produced by humans or other mammals, suggesting that c-di-GMP signalling would be a promising, biofilm-specific drug target with reduced risk of off-target effects, and perhaps less reluctant to cause development of resistance compared with the current antibiotics.

Group members

Assoc Prof. Jens Bo Andersen

Assoc Prof. Louise Dahl Hultqvist

Dr. Michael Graz

Assoc Prof. Katrine Qvortrup

Dr. Charlotte Uldahl Jansen

Dr. Katja Egeskov Grier

Affiliated Prof. Thomas Eiland Nielsen

Paired metagenomic and metatranscriptomic analyses of the Oral Microbiome in health and disease

We are a group of researchers from CBC, Department of Odontology and Globe (University of Copenhagen), ETH Zurich and Singapore Centre for Environmental Life Sciences (SCELSE), who have been working together since 2016 on development and validation of experimental procedures that can reveal on specific bacterial activity in saliva. By determining the mRNA/DNA ratio of every single gene being expressed by deep sequencing approaches, including the required bioinformatics pipeline, we have managed to develop a concomitant metagenomic and metatranscriptomic characterization of the microbiota in clinical (oral) samples.

In 2017, we first demonstrated the efficacy of our approach by differentiating patients with oral diseases, i.e. dental caries and periodontitis from healthy controls. During the period from 2017 to 2020, we continuously refined the bioinformatic pipeline to significantly increase the resolution of our experimental analysis which enabled us to move the focus from phylum to species level.

In 2021, we published two papers on species-specific expression of specific bacterial genes and pathways in biofilms from clinical oral samples. In the first paper, we demonstrated that chronic local inflammation of the oral cavity, periodontitis, affect bacterial gene expression, at other locations of the oral cavity, as determined by a significantly higher expression of genes involved in carbohydrate metabolism in conditions of periodontitis. Subsequently, we focused our analysis on oral streptococci, as these are the main contributors to carbohydrate metabolism in the oral cavity, to reveal that oral bacterial gene expression of oral streptococci is significantly affected by periodontitis.

Collectively, our data analyses indicate that gene expression of specific oral streptococci in saliva can be employed as screening biomarker of oral health status, with a huge translational potential to be used routinely in the future in the dental office for molecular identification of oral disease trajectories at preclinical stages.

Group members

Assoc Prof. Daniel Belstrøm (PI), Dept. of Odontology

Dr. Florentin Constancias, ETH

Assoc Prof. Martin Sikora, Globe

Prof. Michael Givskov, CBC

Prof. Stephan Schuster, Dr. Daniela Moses, and Prof. Liang Yang, SCELSE