Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections
| Autor: | Magee Thomas Victor, Thuy-Trinh Nguyen, Joseph A. Abramite, Yue Shen, Jian Lin, Jiri Aubrecht, Fadia Dib-Hajj, Jeremy T. Starr, Alita A. Miller, Matthew Frank Brown, Shawn H. MacVane, Michael D. Huband, Li Zhang, Karl Granskog, Bryan Li, Jinshan Michael Chen, James M. McKim, John P. O'Donnell, Karen L. Leach, Paul C. Wilga, David P. Nicolau, Sandra P. McCurdy, Mark Edward Flanagan, Antonia F. Stepan, Andrew P. Tomaras, Mark C. Noe, Michael Kuhn, Scott B. Seibel, Rebecca Irvine, Jinfeng Xu, David C. Ackley, David R. Luke, Jared L. Crandon, Joel R. Hardink, Andrew Butler |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.drug_class Polymyxin Microbial Sensitivity Tests medicine.disease_cause Microbiology Dogs Therapeutic index In vivo Gram-Negative Bacteria Drug Discovery medicine Animals Humans Polymyxins Cross Infection biology Chemistry Pseudomonas aeruginosa biology.organism_classification Antimicrobial Drug Resistance Multiple Anti-Bacterial Agents Rats Acinetobacter baumannii Multiple drug resistance beta-Alanine Molecular Medicine Female Polymyxin B medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 56:5079-5093 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages. |
| Databáze: | OpenAIRE |
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