A hybrid experimental-modelling study of SOS response-induced filamentation and its effect on bacterial colony growth

Bacterial resistance to antibiotics is a global problem which is already implicated in many deaths by bacterial infection. Bacteria can evolve resistance through mutations mediated by the DNA damage-induced SOS response, which also results in DNA repair and cell division inhibition. Whilst DNA-damaging antibiotics and UV radiation are known to activate the SOS response, it remains unresolved whether other, non-primarily DNA damaging bactericidal antibiotics are capable of inducing the SOS response. SOS-induced cell division inhibition also leads to changes in cell morphology as the cells become filamentous. In some wild type cells, the SOS response is spontaneously induced, leading to variations in mutations and morphology between cells. In this project, we propose a hybrid experimental and modelling approach. Using single molecule tracking, we will examine SOS responses to different kinds of antibiotics by looking at concentration dynamics of the SOS regulator LexA and expression of its coprotease RecA. We will then use measurements of expression of sulA, which is regulated by LexA and codes for the cell division inhibitor SulA, to produce a mathematical model linking LexA dynamics and the cell filamentation phenotype. Finally, we will take measurements of E. coli bending under mechanical forces using microfluidics, and growth rates when undergoing filamentation, and use this to develop an individual-based computational model of bacterial colony growth that implements filamentation. We will then use this model, combined with standard microbiology experiments, to understand the effect of SOS heterogeneity at the population scale.