Understanding antibiotic tolerance and persistence mechanisms in Pseudomonas aeruginosa hypermutator strains

Pseudomonas aeruginosa is a Gram-negative bacterium that is one of the most common pathogens of people with cystic fibrosis. This organism causes chronic lung infections that are very difficult to eradicate. During long-term, chronic infections, mutations often occur within the P. aeruginosa DNA repair genes, leading to a hypermutator phenotype; these mutant bacteria are more persistent and more antibiotic resistant than their wild-type counterparts. We are currently aiming to understand how hypermutation affects the response to clinically relevant antibiotics (both in mono and combination therapy) in order to optimize treatment regimens. In this project we will identify novel putative antibiotic resistance and/or persistence genes in clinically relevant hypermutator strains and characterize the function of these genes using, directed mutagenesis, heterologous expression, complementation and qRT-PCR together with a range of phenotypic assays including ability to form biofilms and susceptibility to various antibiotics and their combinations. These experiments will identify novel targets of direct relevance to treatment of chronic lung infections in cystic fibrosis patients.