Pyridone-conjugated monobactam antibiotics with gram-negative activity.
Brown MF, Mitton-Fry MJ, Arcari JT, Barham R, Casavant J, Gerstenberger BS, Han S, Hardink JR, Harris TM, Hoang T, Huband MD, Lall MS, Lemmon MM, Li C, Lin J, McCurdy SP, McElroy E, McPherson C, Marr ES, Mueller JP, Mullins L, Nikitenko AA, Noe MC, Penzien J, Plummer MS, Schuff BP, Shanmugasundaram V, Starr JT, Sun J, Tomaras A, Young JA, Zaniewski RP.
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.