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Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations.


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 Escherichia 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 that understanding molecular mechanisms of drug resistance allows us to effectively amplify even small evolutionary vulnerabilities of resistant cells to potentially enhance or enable adaptive therapies by accelerating posttreatment competition between resistant and susceptible cells.

SUBMITTER: Melnikov SV 

PROVIDER: S-EPMC7395499 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations.

Melnikov Sergey V SV   Stevens David L DL   Fu Xian X   Kwok Hui Si HS   Zhang Jin-Tao JT   Shen Yue Y   Sabina Jeffery J   Lee Kevin K   Lee Harry H   Söll Dieter D  

Proceedings of the National Academy of Sciences of the United States of America 20200713 30


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 <i>Escherichia coli</i> as a model, we show that genetic mutati  ...[more]

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