Our team is studying the pharmacology of drugs, mainly anti-infective agents (antibiotics) with the aim to decipher the mechanisms responsible for their activity or their cellular toxicity, and to optimize their use in the clinics (based on a better knowledge of their pharmacodynamics and of the risks for selecting resistance). Disciplines and methodologies used involve biophysics, biochemistry, microbiology, cellular and molecular biology, and morphology.
Our main objectives are to decipher, at the molecular and cellular levels, the mechanisms of the interaction between these drugs and
- bacteria (target cells), with the aim to progress in the understanding of their mode of action and of mechanisms of bacterial resistance;
- host cells, with the aim to unravel the mechanism of their transmembrane transport, and to evaluate the consequences of their cellular accumulation for activity and toxicity.
To this effect, we explore
- at the cellular level, the cellular pharmacokinetics of antibiotics (accumulation, distribution, and efflux in eukaryotic cells), in relation with their activity against intracellular pathogens and with their capacity to cause cellular toxicity (lysosomal or mitochondrial alterations; apoptosis).
- at the molecular level, (i) the interaction between antibiotics and membrane lipids and consequences therof for membrane biophysical properties, (ii) the selection of resistance in vitro (with a particular interest for active efflux), and (iii) the activity of novel antibiotics acting on new, unexploited targets.
Our experimental approaches include:
- biophysical approaches aimed at characterizing at the molecular level the interaction between drugs and membrane lipids and at understanding how biophysics encounters cell functions (cell bacteria division, shaping/reshaping of red blood cells, e.g.);
- genomic and proteomic approaches aimed at evidencing the effects of drugs on the expression and function of target genes/proteins;
- pertinent cellular models for the study of drug pharmacokinetics (accumulation, subcellular distribution, efflux), pharmacodynamics (intracellular infection, biofilm) and cellular toxicity, which are used for exploring the mechanisms governing the interaction between host cells, drugs and bacteria, and to evaluate new molecules or new therapeutic strategies.
In a broader context, our translational research activities include clinical trials aimed at optimizing antibiotic use (adaptation of their mode of administration or daily dosage) with the aim to increase their efficacy and/or reduce their toxicity (run in coworking with different hospitals in Belgium), and collection of clinical isolates for which we study antibiotic resistance and try to establish a potential link with the treatment received by the patient.