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

…, F Dib-Hajj, ME Flanagan, K Granskog…

Index: 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.; Nicolau, David P.; Nguyen, Thuy-Trinh; Noe, Mark C.; O'Donnell, John P.; Seibel, Scott B.; Shen, Yue; Stepan, Antonia F.; Tomaras, Andrew P.; Wilga, Paul C.; Zhang, Li; Xu, Jinfeng; Chen, Jinshan Michael Journal of Medicinal Chemistry, 2013 , vol. 56, # 12 p. 5079 - 5093

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Citation Number: 13

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- ...