title: SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3.
abstract: A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Kerry E
authors.initials: KE
authors.lastname: Murphy-Benenato
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Dangel
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Hajnalka E
authors.initials: HE
authors.lastname: Davis
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Durand-Réville
authors.affiliation: Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Haris
authors.initials: H
authors.lastname: Jahić
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Mueller
authors.affiliation: Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Manyak
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Quiroga
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Rooney
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Sylvester
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Wu
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Zambrowski
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Shannon X
authors.initials: SX
authors.lastname: Zhao
keywords: Pseudomonas aeruginosa; monocarbam; penicillin binding protein; siderophore; structure-guided design; β-lactam