Summary
Antibiotic resistance often causes a fitness cost to bacteria in the absence of the drug. The cost is the main determinant of the prevalence of resistances upon reducing antibiotics use. Understanding its causes is considered the Holy Grail in the antibiotic resistance field. We show that most of the variation in the cost of resistances common in pathogens can be explained by DNA breaks, a previously unsuspected cause. We demonstrate that the cost can be manipulated by targeting the RNase responsible for degrading R-loops, which cause DNA breaks. Indeed, lack of RNase HI drives resistant clones to extinction in populations with high initial frequency of resistance. Thus, RNase HI provides a promising target for antimicrobials specific against resistant bacteria, which we validate using a repurposed drug. These results show previously unknown effects of resistance on bacterial physiology and provide a framework for the development of new strategies against antibiotic resistance.
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