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Published on: March 2, 2020
Pyridone-conjugated monobactam antibiotics with gram-negative activity
Matthew F Brown1, Mark J Mitton-Fry, Joel T Arcari
1Worldwide Medicinal Chemistry, ‡Computational Chemistry, §Antibacterials Research Unit, ∥Pharmacokinetics, Dynamics & Metabolism, ⊥Structural Biology, Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
Abstract:
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.
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