The need for new
antibiotics that address serious Gram-negative
infections is well recognized. Our efforts with a series of novel bacterial type II
topoisomerase inhibitors (NBTIs) led to the discovery of
NBTI 5463, an agent with improved activity over other NBTIs against Gram-negative bacteria, in particular against Pseudomonas aeruginosa (F. Reck, D. E. Ehmann, T. J. Dougherty, J. V. Newman, S. Hopkins, G. Stone, N. Agrawal, P. Ciaccio, J. McNulty, H. Barthlow, J. O'Donnell, K. Goteti, J. Breen, J. Comita-Prevoir, M. Cornebise, M. Cronin, C. J. Eyermann, B. Geng, G. R. Carr, L. Pandarinathan, X. Tang, A. Cottone, L. Zhao, N. Bezdenejnih-Snyder, submitted for publication). In the present work,
NBTI 5463 demonstrated promising activity against a broad range of Gram-negative pathogens. In contrast to
fluoroquinolones, the compound did not form a double-strand
DNA cleavable complex with Escherichia coli
DNA gyrase and
DNA, but it was a potent inhibitor of both
DNA gyrase and E. coli
topoisomerase IV catalytic activities. In studies with P. aeruginosa,
NBTI 5463 was bactericidal. Resistant mutants arose at a low rate, and the mutations were found exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux system.
Levofloxacin-selected resistance mutations in GyrA did not result in decreased susceptibility to
NBTI 5463. Animal
infection studies demonstrated that
NBTI 5463 was efficacious in mouse models of lung, thigh, and ascending
urinary tract infections.