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

Andrei Papkou,Bernadette Young,R Craig Maclean,Jessica Hedge,Natalia Kapel

doi:10.1038/s41467-020-17735-y

Andrei Papkou, Bernadette Young + Show 3 more

Open Access

https://doi.org/10.1038/s41467-020-17735-y

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Abstract

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. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.

Highlights

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 chose to focus on ciprofloxacin because the evolution of ciprofloxacin resistance has played a key role in the success of MRSA lineages[19], and has been associated with poor clinical outcomes for patients infected with CC22 S. aureus[20]
Bacterial population density declined at the start of the experiment due to the bactericidal effects of ciprofloxacin and the population bottlenecking imposed by serially passaging cultures

Summary

Introduction

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 test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. 1234567890():,; Infections caused by antibiotic resistant bacteria are currently estimated to cause ~700,000 deaths per year, and this mortality rate is predicted to increase to 10 million per year by 20501 Given this threat, resistance has been identified as one of the most important challenges to human health by a wide variety of national and international bodies, including the WHO, the G8 and the IMF. We chose to focus on ciprofloxacin because the evolution of ciprofloxacin resistance has played a key role in the success of MRSA lineages[19], and has been associated with poor clinical outcomes for patients infected with CC22 S. aureus[20]

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