Discovery of dual GyrB/ParE inhibitors active against Gram-negative bacteria.

Abstract Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gram-negative bacterial membranes depends on many factors including physicochemical properties of the inhibitors. Herein, we show the optimization of pyridylureas leading to compounds with potent activity against Gram-negative bacterial species such as P.aeruginosa, E.coli and A.baumannii. Graphical abstract Image 1 Highlights • Potent dual inhibitors of Gram-negative GyraseB and ParE enzymes has been identified. • Balancing the basicity and acidity of the groups lead to compounds with good permeability. • Compounds exhibit broad-spectrum activity and 2–8 μg/mL MIC 90 against P.aeruginosa and A.baumannii. [ABSTRACT FROM AUTHOR]