Speaker
Description
Bacteria possess intrinsic resistance mechanisms to antibiotics and also acquire resistance through mutations. While mutations that confer resistance to antibiotics have been well-characterized, intrinsic resistance remains poorly explored. In this study, we ask whether intrinsic mechanisms of resistance may be viable targets for the design of novel therapeutics. Using trimethoprim, an antifolate antibiotic, we performed a genetic screen in Escherichia coli and identified genes involved in cell wall processes, metabolism and transport that modulate intrinsic antibiotic susceptibility. Knockouts of several of these hits could successfully resensitize laboratory evolved trimethoprim resistant strains to trimethoprim treatment. We are currently asking whether these genes may represent potential targets for antibiotic re-sensitization by testing the stability of their phenotypes. Using laboratory evolution, we firstly show that the evolutionary stability of sensitized phenotypes differs for genes from different pathways, and secondly, track genomic changes associated with overcoming antibiotic hypersensitivity.
