Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus

The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. We tested this hypothesis by challenging a diverse set of 222 strains of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. Surprisingly, we found that a single efflux pump, norA, causes widespread variation in evolvability across the diversity of S. aureus. In most lineages of S. aureus, elevated norA expression potentiated evolution by increasing the fitness benefit provided by resistance mutations in DNA topoisomerase under ciprofloxacin treatment. Amplification of norA provided a further mechanism of rapid evolution, but this was restricted to strains from CC398. Crucially, chemically inhibiting NorA effectively prevented the evolution of resistance across the diversity of S. aureus. Our study shows that the underlying genetic diversity of pathogenic bacteria plays a key role in shaping resistance evolution. Understanding this link makes it possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome. Overall design: 14 pairs of high and low evolvability Staphylococcus aureus strains after 1 hour exposure to 1mg/l ciprofloxacin