Understanding and preventing the evolution of antibiotic tolerance

Even though they are not resistant to antibiotics, some bacteria can survive treatment by entering a non-growing 'persister' state. After treatment finishes, the surviving persisters can resume growth, leading to recurring infections, as often observed in urinary tract infections (UTIs). Furthermore, typical once-daily antibiotic dosing schemes can lead to rapid evolution of mutations causing antibiotic tolerance. I will use evolution experiments combined with sequencing to determine how these mutations evolve in E. coli in response to different antibiotics. I will use state-of-the-art single-cell microscopy to understand how different mutations lead to distinct cell states and how cell physiology in turn determines antibiotic susceptibility. Finally, I will analyse the genomes of a unique set of clinical strains to determine how tolerance mutations evolve during treatment of UTIs. This data will be combined to identify new and potentially ground-breaking strategies to minimize antibiotic tolerance during treatment of bacterial infections.