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Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections

2013; American Chemical Society; Volume: 56; Issue: 12 Linguagem: Inglês

10.1021/jm400416u

1520-4804

Thomas V. Magee, Matthew F. Brown, Jeremy T. Starr, David C. Ackley, J. A. Abramite, Jiri Aubrecht, Andrew J. Butler, Jared L. Crandon, Fadia B. Dib-Hajj, Mark E. Flanagan, Karl Granskog, Joel R. Hardink, Michael D. Huband, Rebecca Irvine, Michael Kuhn, Karen L. Leach, Bryan Li, Jian Lin, David R. Luke, Shawn H. MacVane, Alita A. Miller, Sandra P. McCurdy, James M. McKim, David P. Nicolau, Thuy-Trinh Nguyen, Mark C. Noe, John P. O’Donnell, Scott B. Seibel, Yue Shen, Antonia F. Stepan, Andrew P. Tomaras, Paul C. Wilga, Li Zhang, Jinfeng Xu, Jinshan Michael Chen,

Pneumocystis jirovecii pneumonia detection and treatment

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.