A novel strategy has been developed to use compounds as anti-evolution drugs to help combat resistance to antibiotics.
Researchers at the Department of Zoology, University of Oxford, UK, tested the hypothesis that the rise of antibiotic resistance in many pathogens has been driven by the spread of a small number of strains.
This, they say, suggests that some bacteria could be genetically predisposed to evolving resistance.
Writing in Nature Communications, they describe quantifying the differences in evolvability between pathogen strains and searching for “potentiator” genes that accelerate the evolution of resistance.
The researchers challenged more than 200 isolates of Staphylococcus aureus with evolving resistance to the antibiotic ciprofloxacin in the lab and demonstrated that different strains evolve resistance at different rates.
They then used genome resequencing and gene expression profiling to identify key candidate genes that are associated with high evolvability across S.aureus isolates.
By experimenting with genetically engineered strains of S.aureus, the team confirmed the importance of a key candidate gene, norA, which pumps antibiotics out of bacterial cells.
They went on to demonstrate that chemically inhibiting the norA efflux pump can prevent S.aureus from evolving resistance in the lab.
Lead author Professor Craig Maclean said: “Antibiotic efflux increases evolvability by magnifying the benefits of mutations that alter the cellular target of ciprofloxacin. Crucially, understanding this link makes it possible to predict which strains are likely to evolve resistance, and to use efflux pump inhibitors to slow down resistance evolution.
“Whole genome sequencing has revolutionised clinical microbiology, and our study suggests that it might possible to use genomic data to predict which strains of Staphylococcus aureus have a high likelihood of becoming resistant to antibiotics during treatment.
“Our study also shows that using antibiotic adjuvants (in this case, an efflux pump inhibitor) can dramatically slow down the rate at which resistance evolves. A number of efflux pump inhibitors are already available, and our work shows a novel strategy for using these compounds as ‘anti-evolution’ drugs.”
The authors say their study had two limitations: reserpine, the drug they used, is not yet FDA approved, and could not be used in humans, and they say it is possible that anti-evolution drugs may be less effective in vivo because of difficulties in getting both antibiotics and anti-evolution drugs to the same tissues at the same time.
Nevertheless, they hope their results will lead to further research to test the role of efflux pumps in resistance evolution during infections.
Papkou A, Hedge J, Kapel N et al. Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates. Nature Communications 7 August 2020; DOI: 10.1038/s41467-020-17735-y.
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