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

作者：Magee Thomas V^*; Brown Matthew F; Starr Jeremy T; Ackley David C; Abramite Joseph A; Aubrecht Jiri; Butler Andrew; Crandon Jared L; Dib Hajj Fadia; Flanagan Mark E; Granskog Karl; Hardink Joel R; Huband Michael D; Irvine Rebecca; Kuhn Michael; Leach Karen L; Li Bryan; Lin Jian; Luke David R; MacVane Shawn H; Miller Alita A; McCurdy Sandra; McKim James M Jr; Nicolau David P; Thuy Trinh Nguyen; Noe Mark C; O'Donnell John P; Seibel Scott B; Shen Yue

来源：Journal of Medicinal Chemistry, 2013, 56(12): 5079-5093.

DOI：10.1021/jm400416u

We report novel polymyxin analogues with improved antibacterial in vitro potency against polymprin 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.

• 出版日期2013-6-27