Novel antibacterials with activity against the Gram-negative bacteria associated with nosocomial infections, including Escherichia coli and other Enterobacteriaceae, are urgently needed due to the increasing prevalence of multidrug-resistant strains. A major obstacle that has stalled progress on nearly all small-molecule classes with potential for activity against these species has been achieving sufficient whole-cell activity, a difficult challenge due to the formidable outer membrane and efflux barriers intrinsic to these species. Using a set of compound design principles derived from available information relating physicochemical properties to Gram-negative entry or activity, we synthesized and evaluated a focused library of oxazolidinone analogues, a currently narrow spectrum class of antibacterials active only against Gram-positive bacteria. In this series, we have explored the effectiveness for improving Gram-negative activity by identifying and combining beneficial structural modifications in the C-ring region. We have found polar and/or charge-carrying modifications that, when combined in hybrid C-ring analogues, appear to largely overcome the efflux and/or permeability barriers, resulting in improved Gram-negative activity. In particular, those analogues least effected by efflux and the permeation barrier had significant zwitterionic character.
Keywords: Gram-negative; efflux pump; outer membrane permeability; oxazolidinones; porins.