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.
MeSH terms
-
Animals
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / pharmacokinetics
-
Anti-Bacterial Agents / pharmacology*
-
Escherichia coli / drug effects
-
Gram-Negative Bacteria / drug effects*
-
Inhibitory Concentration 50
-
Klebsiella pneumoniae / drug effects
-
Male
-
Microbial Sensitivity Tests
-
Molecular Structure
-
Monobactams / chemistry
-
Monobactams / pharmacokinetics
-
Monobactams / pharmacology*
-
Pseudomonas aeruginosa / drug effects
-
Pyridones / chemistry
-
Pyridones / pharmacokinetics
-
Pyridones / pharmacology*
-
Rats
-
Rats, Wistar
Substances
-
Anti-Bacterial Agents
-
Monobactams
-
Pyridones