1416048-47-9Relevant articles and documents
Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant gram-negative nosocomial infections
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
, p. 5079 - 5093 (2013/07/26)
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.
