Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections.

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, 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

Index: J. Med. Chem. 56(12) , 5079-93, (2013)

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Abstract

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.