Our research
Bacteria cause many of the most devastating infectious diseases posing a major societal and economic burden. The spread of antibiotic resistance amongst bacterial pathogens is causing widespread alarm. A multitude of societal and scientific strategies are needed in order to tackle the threat caused by pathogenic bacteria. One vital strategy is to develop new pharmaceuticals that specifically neutralize the bacterial pathogen and thereby prevent or treat the infectious disease.
TCML aims to understand the interaction of bacterial pathogens with their host cells at molecular level. Our research is focused on proteins, in particular on enzymes, of the bacterial pathogen and of the host cell that are key molecular players shaping the development and severity of an infectious disease. We utilize animal experimentation, cell culture models and a range of biochemical and biophysical methods of protein chemistry to understand bacterial infection at the molecular level. The obtained basic research knowledge is the key to develop new antibacterial pharmaceuticals.
Research topics at TCML
Bacterial exotoxins
Many bacterial pathogens cause the infectious disease because they produce exotoxins that damage host cells. First, we generate new research knowledge on how the exotoxins work upon host cell recognition and execution of their cytotoxic functions. Secondly, we develop inhibitors of bacterial exotoxins. We have a major interest on exotoxins that act as NAD+ consuming enzymes inside the host cell, an activity frequently associated with covalent modification of host cell proteins via ADP-ribosylation.
Bacterial toxin-antitoxin systems
Bacterial toxin-antitoxin systems are widely distributed genetic elements that encode for a protein toxin that inhibits the growth of the toxin-expressing bacterium and either a protein- or an RNA-based antitoxin that blocks the activity of the toxin. The reason why bacteria have these systems with strong self-toxigenic properties is an enigma. First, we generate new research knowledge on how the toxins work and aim to understand the reasons why do they exist. Secondly, we develop small molecular weight compound inhibitors of toxin-antitoxin interaction to unleash the strong bactericidal activity of the toxin. We have a major interest on toxins that act as NAD+ consuming enzymes inside the bacterial cell.
Host cell enzymes that are homologs of bacterial exotoxins
Individual host cells have a remarkable ability to sense their external and internal environments and then to act on the gathered information. Primarily, this task is achieved by changes in protein activities and in interactions between different proteins, both regulated by post-translational modifications. First, we generate new research knowledge on how the host cell enzymes that catalyze post-translational modifications work in an infectious disease. Secondly, we investigate whether pharmacological targeting of these host cell enzymes is beneficial in an infectious disease. We have a major interest on host cell proteins that act as cytosolic NAD+ consuming enzymes, i.e. homologs of bacterial exotoxins, frequently associated with covalent modification of host cell proteins via ADP-ribosylation.
Evolution of bacterial pathogens
Elaborate molecular interactions between the bacterium and the host determine the outcome of exposure across the continuum of asymptomatic colonization and acute life-threatening infection. Protein-protein interactions and enzyme activities play a key role. First, we utilize modern DNA sequencing technologies to characterize bacterial diversity at whole genome level in clinical and wild-life samples. Secondly, we relate the mutation diversity landscapes with the functions of bacterial virulence factors via functional genomics and evolutionary selection pressure analyses. We have a major interest on bacterial exotoxins with an overall aim to understand the functional constrains of bacterial pathogen evolution at molecular level.
