title: Discovery of efficacious Pseudomonas aeruginosa-targeted siderophore-conjugated monocarbams by application of a semi-mechanistic pharmacokinetic/pharmacodynamic model.
abstract: To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.
authors: Infection Innovative Medicines and ‡Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors: Kerry E
authors: KE
authors: Murphy-Benenato
authors: Pratik R
authors: PR
authors: Bhagunde
authors: April
authors: A
authors: Chen
authors: Hajnalka E
authors: HE
authors: Davis
authors: Thomas F
authors: TF
authors: Durand-Réville
authors: David E
authors: DE
authors: Ehmann
authors: Vincent
authors: V
authors: Galullo
authors: Jennifer J
authors: JJ
authors: Harris
authors: Holia
authors: H
authors: Hatoum-Mokdad
authors: Haris
authors: H
authors: Jahić
authors: Aryun
authors: A
authors: Kim
authors: M R
authors: MR
authors: Manjunatha
authors: Erika L
authors: EL
authors: Manyak
authors: John
authors: J
authors: Mueller
authors: Sara
authors: S
authors: Patey
authors: Olga
authors: O
authors: Quiroga
authors: Michael
authors: M
authors: Rooney
authors: Li
authors: L
authors: Sha
authors: Adam B
authors: AB
authors: Shapiro
authors: Mark
authors: M
authors: Sylvester
authors: Beesan
authors: B
authors: Tan
authors: Andy S
authors: AS
authors: Tsai
authors: Maria
authors: M
authors: Uria-Nickelsen
authors: Ye
authors: Y
authors: Wu
authors: Mark
authors: M
authors: Zambrowski
authors: Shannon X
authors: SX
authors: Zhao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008297:Male; D008997:Monobactams / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017262:Siderophores / Q000378:metabolism*; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D008997:Monobactams; D017262:Siderophores; D001618:beta-Lactamases