The role of ROS and genome plasticity during de novo acquisition of antibiotic resistance

Antibiotic resistance is considered one of the major dangers threatening human health. Bacteria initially susceptible to antibiotics can develop resistance through adaptation on a phenotypic level, horizontal gene transfer, or de novo acquisition of resistance. Sublethal concentrations in the environment are an important factor driving both the emergence and spread of antibiotic resistance. Fundamental knowledge about the molecular mechanisms driving acquisition of de novo antibiotic resistance are necessary to design interventions that can interfere with or impair development of resistance. In this thesis, these molecular mechanisms that drive development of resistance are studied, with particular focus on two aspects: the role of ROS, and the relevance of genome plasticity during acquisition of resistance. In Chapter 2, the effects of stress on development of antibiotic resistance ware explored, with focus on pH regulation, oxidative stress, and outer porin function. The role of oxidative stress is further investigated in Chapter 3. Chapter 4 and 5 are used to present an overview of all genomic changes that accompany development of a single or double resistance. In chapter 6, the effect of oxygen availability on acquisition of resistance is explored. Chapter 7 is used to discuss the results presented in the preceding chapters. Finally, in Chapter 8, the applicability of the obtained results for veterinary use of antibiotics is outlined.