Cell and Developmental Biology Commons^™

Identification Of A Novel Polyamine Scaffold With Potent Efflux Pump Inhibition Activity Toward Multi-Drug Resistant Bacterial Pathogens, Renee Fleeman, Ginamarie Debevec, Kirsten Antonen, Jessie Adams, Radleigh G. Santos, Gregory S. Welmaker, Richard A. Houghten, Marc A. Guilianotti, Lindsey N. Shaw

Molecular Biosciences Faculty Publications

We have previously reported the use of combinatorial chemistry to identify broad-spectrum antibacterial agents. Herein, we extend our analysis of this technology toward the discovery of anti-resistance molecules, focusing on efflux pump inhibitors. Using high-throughput screening against multi-drug resistant Pseudomonas aeruginosa, we identified a polyamine scaffold that demonstrated strong efflux pump inhibition without possessing antibacterial effects. We determined that these molecules were most effective with an amine functionality at R1 and benzene functionalities at R2 and R3. From a library of 188 compounds, we studied the properties of 5 lead agents in detail, observing a fivefold to eightfold decrease …