Horizontal transfer, selection and maintenance of antibiotic resistance determinants

Abstract

Scientific abstract Antibiotic resistance, especially in Gram-negative pathogens, represents a substantial clinical and financial burden to our society. The presented work investigated mechanisms and evolutionary dynamics that promote the emergence and maintenance of resistance in bacteria. In the first study, conserved collateral susceptibility changes were identified across resistant uropathogenic Escherichia coli, which included also changes towards increased sensitivity of these isolates to certain antibiotics. This so-called collateral sensitivity potentiated the effect of antibiotics and prevented the selection of resistant isolates compared to wildtype strains. The mechanism and fitness cost of resistance were important predictors of collateral responses in resistant bacteria, and their rapid clinical identification could inform future evolution-based infection treatment. The second study demonstrated the potential of a transposable element (Tn1) to spread antibiotic resistance during natural transformation of Acinetobacter baylyi. In the course of this horizontal gene transfer mechanism, Tn1-containing DNA entered the bacterial cell, and specific host, as well as transposon proteins, facilitated Tn1-insertion into the recipient chromosome. A mechanistic model of transposition-mediated natural transformation from a circular, cytoplasmic intermediate is presented. In the third study, uropathogenic E. coli improved its permissiveness towards two unrelated multidrug resistance plasmids while adapting to a new environmental niche. Mutations in the CCR and ArcAB regulatory systems resulted in transcriptional downregulation of plasmid genes and explained plasmid cost reduction. The presented evolutionary dynamics improve our understanding of successful associations between bacterial pathogens and resistance plasmids and provide a novel solution to the so-called ‘plasmid paradox’. In a broader perspective, the findings of this thesis advanced our knowledge on the selection, spread and maintenance of antibiotic resistance in bacteria, which is important to counteract its evolution.