Structure-Uptake Relationship Studies of Oxazolidinones in Gram-negative ESKAPE Pathogens

To date, little is known about applicability and/or generality of molecular features and how they impact small molecule permeation into Gram-negative bacteria. Identifying motifs or structural trends that correlate with broad and/or species-specific permeation would enable the rational design of new antibacterials. The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. E. coli, A. baumannii , and P. aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer-membrane and/or enhance efflux susceptibility broadly and specifically between species. The results of this study illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogs ( 3e , 12f , and 14 ) were identified from this study that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.