Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations
Sergey Melnikov, David L. Stevens, Xian Fu, Hui Si Kwok, Jintao Zhang, Yue Shen, Jeffery Sabina, Kevin Lee, Harry Lee, Dieter Söll
Abstract
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.