NBTI 5463 Is a Novel Bacterial Type II Topoisomerase Inhibitor with Activity against Gram-Negative Bacteria and In Vivo Efficacy
| Autor: | Sussie Hopkins, David E. Ehmann, Mark Cronin, Folkert Reck, Adam B. Shapiro, Gregory G. Stone, Thomas J. Dougherty, Michele Johnstone, Asha S. Nayar, Joseph V. Newman |
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| Rok vydání: | 2014 |
| Předmět: |
DNA Topoisomerase IV
Gram-negative bacteria Topoisomerase IV Morpholines Microbial Sensitivity Tests medicine.disease_cause DNA gyrase Microbiology Gram-Negative Bacteria Escherichia coli medicine Topoisomerase II Inhibitors Experimental Therapeutics Pharmacology (medical) Naphthyridines Pharmacology biology Errata Pseudomonas aeruginosa biology.organism_classification Anti-Bacterial Agents Infectious Diseases DNA Gyrase biology.protein Efflux Topoisomerase-II Inhibitor Type II topoisomerase Fluoroquinolones |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 58:4250-4250 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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