Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections
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- 作者：Thomas V. Magee ; Matthew F. Brown ; Jeremy T. Starr ; David C. Ackley ; Joseph A. Abramite ; Jiri Aubrecht ; Andrew Butler ; Jared L. Crandon ; Fadia 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 McCurdy ; James M. McKim ; Jr. ; David P. Nicolau ; Thuy-Trinh Nguyen ; Mark C. Noe ; John P. O鈥橠onnell ; Scott B. Seibel ; Yue Shen ; Antonia F. Stepan ; Andrew P. Tomaras ; Paul C. Wilga ; Li Zhang ; Jinfeng Xu ; Jinshan Michael Chen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 27, 2013
- 年：2013
- 卷：56
- 期：12
- 页码：5079-5093
- 全文大小：415K
- 年卷期：v.56,no.12(June 27, 2013)
- ISSN：1520-4804
文摘
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鈥搕oxicity 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.