Structure guided design, synthesis and characterization of inhibitors of the bacterial enoyl-ACP reductase Fab1

MEDI 325

Judd Berman, jberman@dalton.com, Dalton Pharma Services, 349 Wildcat Rd, Toronto, ON M3J 2S3, Canada
There is a pressing need for new antibacterial agents that act via new targets. Bacterial fatty acid biosynthesis enzymes offer such an opportunity. In certain pathogenic bacteria the enoyl-acyl carrier protein (ACP) reductase FabI is responsible for the terminal step in fatty acid biosynthesis and its corresponding gene is essential (similar transformations in humans are carried out by a single multifunctional enzyme designated FAS1). This has led to the pursuit of specific enoyl-ACP reductase inhibitors of FabI as novel antibacterial agents. Structure guided design and synthesis of a series of ene-amide inhibitors of FabI will be described. High resolution 3-dimensional structures of FabI from S. aureus and the Class A pathogen F. Tularensis provide a detailed understanding of the structural factors governing ligand recognition. The potent antibacterial activity of these compounds will be presented.