title: NBTI 5463 is a novel bacterial type II topoisomerase inhibitor with activity against gram-negative bacteria and in vivo efficacy.
abstract: 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.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dougherty
authors.forename: Asha
authors.initials: A
authors.lastname: Nayar
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
authors.forename: Sussie
authors.initials: S
authors.lastname: Hopkins
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Stone
authors.forename: Michele
authors.initials: M
authors.lastname: Johnstone
authors.forename: Adam B
authors.initials: AB
authors.lastname: Shapiro
authors.forename: Mark
authors.initials: M
authors.lastname: Cronin
authors.forename: Folkert
authors.initials: F
authors.lastname: Reck
authors.forename: David E
authors.initials: DE
authors.lastname: Ehmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D024841:Fluoroquinolones / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009025:Morpholines / Q000494:pharmacology*; D009287:Naphthyridines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009025:Morpholines; C000600719:NBTI 5463; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase