Natural polymorphisms in Pseudomonas aeruginosa populations reveal a dual role for DNA gyrase in fluoroquinolone resistance and persistence

A genetic atlas of bacterial antibiotic survival could inform clinical decisions offering novel therapeutic options and improving treatment success. While antibiotic resistance is well-studied, persistence remains poorly understood, particularly in the context of the vast natural strain diversity among pathogens. Here, we investigated both phenotypes in over 350 diverse, natural isolates of Pseudomonas aeruginosa. Resistance and persistence positively correlate and increase in strains with a life history of high antibiotic exposure, such as those isolated after commercial antibiotic introduction. These two strategies are therefore not mutually exclusive and likely share selective pressures. Unexpectedly, genome-wide associations also reveal molecular links between resistance and persistence. While DNA gyrase mutations have traditionally been associated with antibiotic resistance, our findings show that their dominant role lies in controlling bacterial persistence by reducing DNA damage responses and autolysis. Notably, mutations in gyrA increase persistence across diverse Gram-negative species while simultaneously facilitating the evolution of resistance. Thus, efficient targeting of DNA gyrase may offer a dual therapeutic advantages by impeding both persistence and resistance development.