Pharmacokinetics and pharmacodynamics of antibiotics in model of persistent infections

Bruxelles Woluwe

Bacterial persistent or recurrent infections are associated with two specific lifestyles, namely intracellular survival and biofilms. We are studying antibiotic activity against these two forms of infections in relationship with antibiotic pharmacokinetics (factors determining antibiotic access to the target).

  1. Cellular pharmacokinetics
    We study the cellular accumulation (including the mechanisms of entry) and the subcellular localization of novel molecules in preclinical and clinical development, as a basis for further studies examining their intracellular activities in specific compartments. We try to decipher the mechanisms for their penetration and distribution within the cells. Over the last years, we have focused our interest on new antibiotic classes, like lipoglycopeptides, ketolides, new fluoroquinolones and new oxazolidinones now present on the market. are now examining innovative antibiotic classes acting on still unexploited targets in order to define their capacity to accumulate within the cells and then to define their interest for the treatment of intracellular infections.
  2. Cellular pharmacodynamics
    In parallel, we study the activity of antibiotics against intracellular bacteria sojourning in different subcellular compartments, mainly Listeria mono-cytogenes (cytosol), Staphylococcus aureus (phagolysosomes), and Pseudomonas aeruginosa. We have also extended this model to other bacterial species of medical interest. We developed an in vitro pharmacodynamic approach to compare the efficacy and the potency of the drugs. In brief, we showed that antibiotics are in general less effective but equipotent against intracellular than against extracellular bacteria, irrespective of their accumulation level. The data generated with these models have been incorporated in the dossier having led to the registration of the last antibiotics brought on the market.

We are now trying to elucidate the mechanisms by which intracellular bacteria become tolerant to antibiotics. We specifally focus on trying to identify genes involved in intracellular persistence. To this effect, we are running transcriptomic analyses on intracellular S. aureus surviving antibiotic exposure within permissive eukaryotic cells and are chacarterizing the capacity to survie inside these cells of clinical isolates collected from persistent infections.