title: Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections.
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.
authors.affiliation: Pfizer Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut 06340, USA. thomas.v.magee@pfizer.com
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Magee
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Starr
authors.forename: David C
authors.initials: DC
authors.lastname: Ackley
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Abramite
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: Andrew
authors.initials: A
authors.lastname: Butler
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Fadia
authors.initials: F
authors.lastname: Dib-Hajj
authors.forename: Mark E
authors.initials: ME
authors.lastname: Flanagan
authors.forename: Karl
authors.initials: K
authors.lastname: Granskog
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.forename: Rebecca
authors.initials: R
authors.lastname: Irvine
authors.forename: Michael
authors.initials: M
authors.lastname: Kuhn
authors.forename: Karen L
authors.initials: KL
authors.lastname: Leach
authors.forename: Bryan
authors.initials: B
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: David R
authors.initials: DR
authors.lastname: Luke
authors.forename: Shawn H
authors.initials: SH
authors.lastname: MacVane
authors.forename: Alita A
authors.initials: AA
authors.lastname: Miller
authors.forename: Sandra
authors.initials: S
authors.lastname: McCurdy
authors.forename: James M
authors.initials: JM
authors.lastname: McKim
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Thuy-Trinh
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Noe
authors.forename: John P
authors.initials: JP
authors.lastname: O'Donnell
authors.forename: Scott B
authors.initials: SB
authors.lastname: Seibel
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Tomaras
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wilga
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Jinshan Michael
authors.initials: JM
authors.lastname: Chen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D003428:Cross Infection / Q000188:drug therapy*; D004285:Dogs; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D011113:Polymyxins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D011113:Polymyxins; D015091:beta-Alanine; C011757:2,3-diaminopropionic acid