Investigation of the Mechanism of Action of Oxazolidinones

The need to develop broad spectrum antibacterial agents is urgent as multidrug resistant bacteria have emerged in hospitals worldwide. The number of efficacious antibiotics is diminishing because bacteria develop mechanisms to confer resistance. Oxazolidinones work by interfering with protein translation and are mainly active against gram‐positive bacteria. The Aggen research group at Northeastern University is focused on optimizing the properties of oxazolidinones to be able to penetrate the lipopolysaccharide layer of gram‐negative bacteria while maintaining their target potency. The rational lead optimization campaign based on the linezolid scaffold, involves keeping a low molecular weight (MW<400), and high polarity (ClogD <1) to allow passage through the porins and to be able to escape the bacterial efflux pumps. The goal is to determine the mechanism of action of oxazolidinones in order to provide insight into the development of the next‐generation oxazolidinones. We aim to determine the effect of oxazolidinones on the translation function of ribosomes, defining which step of translation is inhibited and determining the binding site of the novel oxazolidinones.