Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity

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• 作者：Matthew F. Brown ; Mark J. Mitton-Fry ; Joel T. Arcari ; Rose Barham ; Jeffrey Casavant ; Brian S. Gerstenberger ; Seungil Han ; Joel R. Hardink ; Thomas M. Harris ; Thuy Hoang ; Michael D. Huband ; Manjinder S. Lall ; M. Megan Lemmon ; Chao Li ; Jian Lin ; Sandra P. McCurdy ; Eric McElroy ; Craig McPherson ; Eric S. Marr ; John P. Mueller ; Lisa Mullins ; Antonia A. Nikitenko ; Mark C. Noe ; Joseph Penzien ; Mark S. Plummer ; Brandon P. Schuff ; Veerabahu Shanmugasundaram ; Jeremy T. Starr ; Jianmin Sun ; Andrew Tomaras ; Jennifer A. Young ; Richard P. Zaniewski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5541-5552
• 全文大小：536K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

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.