The role of bacterial persistence in the evolvability of antibiotic resistance
Antibiotic resistance is one of the main challenges facing humanity today. Recent work has shown that the evolution of resistance is significantly enhanced by persistence, a phenomenon where bacterial populations produce a small number of dormant cells that can survive transient antibiotic exposure. However, the evolutionary mechanisms responsible for this link are still unclear. In this project, I will develop evolutionary models to investigate two hypotheses to explain this phenomenon: 1) due to low metabolic activity, persisters can accumulate relatively many mutations with limited fitness consequences, thus allowing wider exploration of evolutionary paths to resistance, and 2) because of their phenotypic heterogeneity, persisters allow mutations to be expressed in a wider range of transcriptional backgrounds, allowing a more effective search for solutions to antibiotic stress. I will develop evolutionary models to investigate if, to what extent, and under which conditions (e.g. antibiotic treatment regimens) persistence facilitates evolvability of resistance through these mechanisms. I will use a step-by-step modelling strategy, starting with simple models to assess the general evolutionary dynamics and gradually increase complexity, including explicit gene regulatory networks in final models. This will result in a comprehensive theory of the role of persistence in resistance evolution, providing a basis for new strategies to combat the evolution of antibiotic resistance.