Synthesis and Characterization of Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Antibacterial Activity against Gram-Negative Bacteria

There is an urgent unmet medical
need for novel antibiotics that
are effective against a broad range of bacterial species, especially
multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial
type II topoisomerases (DNA gyrase and topoisomerase IV) display potent
activity against Gram-positive pathogens and no target-mediated cross-resistance
with fluoroquinolones. We report our research efforts aimed at expanding
the antibacterial spectrum of this class of molecules toward difficult-to-treat
Gram-negative pathogens. Physicochemical properties (polarity and
basicity) were considered to guide the design process. Dibasic tetrahydropyran-based
compounds such as 6 and 21 are potent inhibitors
of both DNA gyrase and topoisomerase IV, displaying antibacterial
activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter
baumannii). Compounds 6 and 21 are
efficacious in clinically relevant murine infection models.