title: Pyridone-conjugated monobactam antibiotics with gram-negative activity.
abstract: Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
authors.affiliation: Worldwide Medicinal Chemistry, ‡Computational Chemistry, §Antibacterials Research Unit, ∥Pharmacokinetics, Dynamics & Metabolism, ⊥Structural Biology, Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mitton-Fry
authors.forename: Joel T
authors.initials: JT
authors.lastname: Arcari
authors.forename: Rose
authors.initials: R
authors.lastname: Barham
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Casavant
authors.forename: Brian S
authors.initials: BS
authors.lastname: Gerstenberger
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Harris
authors.forename: Thuy
authors.initials: T
authors.lastname: Hoang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Lall
authors.forename: M Megan
authors.initials: MM
authors.lastname: Lemmon
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Sandra P
authors.initials: SP
authors.lastname: McCurdy
authors.forename: Eric
authors.initials: E
authors.lastname: McElroy
authors.forename: Craig
authors.initials: C
authors.lastname: McPherson
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: John P
authors.initials: JP
authors.lastname: Mueller
authors.forename: Lisa
authors.initials: L
authors.lastname: Mullins
authors.forename: Antonia A
authors.initials: AA
authors.lastname: Nikitenko
authors.forename: Mark C
authors.initials: MC
authors.lastname: Noe
authors.forename: Joseph
authors.initials: J
authors.lastname: Penzien
authors.forename: Mark S
authors.initials: MS
authors.lastname: Plummer
authors.forename: Brandon P
authors.initials: BP
authors.lastname: Schuff
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Starr
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.forename: Andrew
authors.initials: A
authors.lastname: Tomaras
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Young
authors.forename: Richard P
authors.initials: RP
authors.lastname: Zaniewski
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D008997:Monobactams / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D008997:Monobactams; D011728:Pyridones