Staphylococcus aureus mutants resistant to the feed-additive monensin show increased virulence and altered purine metabolism
Ionophores are antibacterial compounds that affect bacterial growth by changing intracellularconcentrations of the essential cations, sodium and potassium. They are extensively used inanimal husbandry to increase productivity and reduce infectious diseases, but ourunderstanding of the potential for and effects of resistance development to ionophores ispoorly known. Thus, given their widespread global usage, it is important to determine thepotential negative consequences of ionophore use on human and animal health. In this study,we demonstrate that exposure to the ionophore monensin can select for resistant mutants inthe human and animal pathogen Staphylococcus aureus, with a majority of the resistantmutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencingand proteomics analysis of the resistant mutants show that the resistance phenotype isassociated with de-repression of de novo purine synthesis, which could be achieved throughmutations in different transcriptional regulators including mutations in the gene purR, therepressor of the purine de novo synthesis pathway. This study shows that mutants withreduced susceptibility to the ionophore monensin can be readily selected and highlights anunexplored link between ionophore resistance, purine metabolism and fitness in pathogenicbacteria.