A mechanistic model of Rtc-regulated RNA repair suggests molecular targets to potentiate antibiotic effects

RNA is susceptible to damage from various internal and external factors. Given the integral role of RNA, its repair is essential for maintaining proper cell function. A highly conserved RNA repair system, the Rtc system, maintains core RNA components of the translational apparatus. In E. coli, Rtc expression is induced upon various stresses, including exposure to ribosome-targeting antibiotics. Its expression enables cells to rescue growth and survive treatment by conferring transient resistance to these antibiotics. The mechanisms by which Rtc-induced resistance arises are largely unknown. Here, we develop and analyse a computational model of Rtc-regulated maintenance of long-lived RNAs that form part of the translational apparatus. Our model analysis and experimental validation provide evidence of cell-to-cell heterogeneity in rtc expression and effects on the translational capacity of cells, indicating that individual cell fates determine antibiotic efficacy and thus rtc may induce a form of heteroresistance. Through further analysis and quantification of single-cell ribosome levels, we then identify targets within the Rtc system that can reduce translational capacity of cells, rendering cells more susceptible and so potentiating antibiotic effects. Our results provide novel tools for the systems analysis of Rtc-regulated RNA repair, they reveal a complex response underpinning resistance conferred by the innate repair system, and they suggest novel avenues to address resistance in E. coli and related clinical pathogens.