SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3.

Autor:	Murphy-Benenato KE; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Dangel B; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Davis HE; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Durand-Réville TF; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Ferguson AD; Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Gao N; Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Jahić H; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Mueller JP; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Manyak EL; Structure and Biophysics, and Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Quiroga O; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Rooney M; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Sha L; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Sylvester M; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Wu F; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Zambrowski M; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Zhao SX; Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Mar 22; Vol. 6 (5), pp. 537-42. Date of Electronic Publication: 2015 Mar 22 (Print Publication: 2015).
DOI:	10.1021/acsmedchemlett.5b00026
Abstrakt:	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.
Databáze:	MEDLINE
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