Exploiting evolutionary trade-offs to combat antibiotic resistance

Melnikov, S. V.; Stevens, D. L.; Fu, X.; Kwok, H. S.; Zhang, J.-T.; Shen, Y.; Sabina, J.; Lee, K.; Lee, H.; Soll, D.

doi:10.1101/2020.01.20.912303

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bioRxiv · 10.1101/2020.01.20.912303

Exploiting evolutionary trade-offs to combat antibiotic resistance

Melnikov, S. V.·Stevens, D. L.·Fu, X.·Kwok, H. S.·Zhang, J.-T.·Shen, Y.·Sabina, J.·Lee, K.·Lee, H.·Soll, D.

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Abstract

Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistant E. coli as a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates a potentially generalizable approach for combating therapeutic resistance, prolonging the effectiveness of drugs and enabling the use of drugs that are no longer effective due to the rapid evolution of resistance.

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Melnikov, S. V., Stevens, D. L., Fu, X., Kwok, H. S., Zhang, J.-T., Shen, Y., Sabina, J., Lee, K., Lee, H., Soll, D.. 2020-01-20. Exploiting evolutionary trade-offs to combat antibiotic resistance. https://doi.org/10.1101/2020.01.20.912303

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