Abstract
Multidrug-resistant bacteria reduce the number of available medications that can treat resistant infections. In the United States, nearly 36,000 deaths per year are caused by antibiotic-resistant infections. To stop or slow down the evolution of the resistance, it is crucial to explore and understand the underlying molecular mechanism driving evolution of resistance. Here, utilizing a saturation mutagenesis library of TEM-1 beta lactamase, we systematically investigate resistance conferring mutations and biophysical changes as a result of these mutations. We employ a high-throughput sequencing based fitness assays and atomic scale molecular dynamic simulations. By systematically studying resistance conferring mutations and epistatic interactions between these mutations, we uncover evolutionary patterns and tradeoffs that can be utilized for developing rational antibiotic treatment strategies that can impede evolution of antibiotic resistance.
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