Evolution of polyamine resistance in <i>Staphylococcus aureus</i> through modulation of potassium transport

<i>Staphylococcus aureus</i> is a leading cause of infectious disease-related deaths globally. Understanding factors that govern adaptation and survival of <i>S. aureus</i> and other pathogens in the host environment is critical for improving infection outcomes. It has been known for several years that <i>S. aureus</i> is highly sensitive to polyamines, a broadly produced class of molecules that play important cellular functions across bacteria and eukaryotes. How <i>S. aureus</i> is capable of adapting to polyamine toxicity remains largely mysterious. Using experimental evolution, our study reveals that changes in potassium transport are sufficient to confer high-level polyamine resistance in <i>S. aureus</i> while simultaneously increasing resistance to unrelated classes of clinically used antibiotics. Our results identify new roles for bacterial potassium transport in polyamine resistance as well as highlighting the utility of experimental evolution for identifying new genetic determinants of pathogen adaptation.