FORINGEN

RESEARCH NETWORK FOR INFECTOGENOMICS

DT-6 Antibiotic resistance of Pseudomonas aeruginosa from Cystic Fibrosis patients

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population arising from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction leads to the secretion of a hyperosmolar, viscous mucus and an impaired function of many CFTR expressing organs (in particular respiratory tract and gastrointestinal tract). In the respiratory tract impaired anti-infective defense results in the promotion of chronic lung infections, predominantly by Pseudomonas aeruginosa (PA). The recurrent administration of antibiotics (systemically or by inhalation) is an important approach in the treatment of respiratory infections of CF patients. Despite its in vitro susceptibility, PA commonly persists in the CF-lung leading to a progressive destruction of lung tissue. It has been suggested that the persistence of PA in the CF-lung is mainly associated with the formation of biofilms (microcolony-like aggregates) characterized by a reduced antimicrobial susceptibility. The aim of this application is to characterize the machanisms of antibiotic tolerance of PA in the CF lung to identify new targets for anti-pseudomonal therapy. During routine microbiological testing of antibiotics conditions completly different from the in vivo situation are applied. In this project we would like to evaluate new approaches for the antimicrobial susceptibility testing which are as close as possible to the in vivo situation. For this we apply the 3 dimensional extracellular matrix collagengel (3D-ECM gel) mimicking the oxygen limited conditions in the CF lung. We would like to determine the concentration dependant efficacy of antimirobial agents (e.g. tobramycin) and the mechansims contributing to increased antibiotic tolerance of PA in the CF lung in order to validate the 3D-ECM gel for routine antimicrobial susceptibility testing.