Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections.
Basic Information
ID: ALA2396592
Journal: J Med Chem
Title: Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections.
Authors: Magee TV, Brown MF, Starr JT, Ackley DC, Abramite JA, Aubrecht J, Butler A, Crandon JL, Dib-Hajj F, Flanagan ME, Granskog K, Hardink JR, Huband MD, Irvine R, Kuhn M, Leach KL, Li B, Lin J, Luke DR, MacVane SH, Miller AA, McCurdy S, McKim JM, Nicolau DP, Nguyen TT, Noe MC, O'Donnell JP, Seibel SB, Shen Y, Stepan AF, Tomaras AP, Wilga PC, Zhang L, Xu J, Chen JM.
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.
CiteXplore: 23735048
DOI: 10.1021/jm400416u
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