UAC Webinar: Investigations of a model case of antibiotic resistance in a bacterial infection model

Investigations of a model case of antibiotic resistance in a bacterial infection model

Persistent bacterial infections caused by opportunistic pathogens have become a serious global health problem. We have for several years investigated - as a model system - airway infections caused by the environmental Pseudomonas aeruginosa bacterial strains in people with the genetic disorder Cystic Fibrosis (CF). Based on a systematically collected biobank of bacterial isolates, including many hundred genome sequenced strains, we have mapped adaptive pathways taken by several clones over decades of colonization in human airways. From a list of the most frequently mutated genes (patho-adaptive mutations) identified during the early years of colonization, it was observed that about 40% of all collected CF isolates harbored mutations in the mexZ gene. The MexZ protein is a negative regulator of an efflux pump (mexX, mexY), frequently associated with antibiotic resistance. Determining the MIC change induced by the mexZ mutations, however, suggested that phenotypic consequences alternative to antibiotic resistance might drive the strong selection for these variants. The recent introduction of a novel laboratory infection model based of differentiated epithelial tissue cell cultures allowed us to investigate bacterial colonization patterns of various P. aeruginosa variant strains - including mexZ mutants - and the finding from these investigations offered new and more plausible explanations for the strong in vivo selection for knock-out of the mexZ gene.