Mining the Magic Mountain for novel antibacterial agents: Slow onset inhibitors of the enoyl reductase enzymes from Mycobacterium tuberculosis and Francisella tularensis

MEDI 324

Peter J. Tonge, peter.tonge@sunysb.edu1, Christopher am Ende2, Hao Lu1, Kathleen Bostrom3, Susan Knudson4, Nina Liu1, Todd J. Sullivan1, Francis Johnson1, Richard A. Bowen4, Sylvia Luckner5, Caroline Kisker6, and Richard A. Slayden3. (1) Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, (2) Department of Chemistry, SUNY Stony Brook, Stony Brook, NY 11794-3400, (3) Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, (4) Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, (5) Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Wurzburg, Wurzburg, 97078, Germany, (6) Institute for Structural Biology, University of Wurzburg, Wurzburg, Germany
Novel chemotherapeutics are needed for treating infectious diseases caused by pathogens such as multi-drug resistant M. tuberculosis as well as the category A agent Francisella tularensis (Ftu). Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of the fatty acid biosynthesis enoyl reductase enzymes (FabIs) from M. tuberculosis (Mtb; MtbFabI; InhA) and Ftu (FtuFabI). The compounds have been designed to cause ordering of the FabI active site loop, based on the premise that loop ordering is coupled to slow-onset enzyme inhibition. While several nanomolar inhibitors of either ftuFabI or MtbFabI were identified, those targeting ftuFabI were slow onset inhibitors while those targeting MtbFabI were not. The mtbFabI inhibitors inhibit the growth of both drug sensitive and isoniazid-resistant MTB strains with MIC90 values of 3-4 ėg mL-1. In addition, the slow onset ftuFabI inhibitors had MIC90 values of < 0.06 ėg mL-1 against the LVS strain of ftu. Significantly, the most potent compounds are highly active in the F. tularensis murine model of infection at 200 mg kg-1. The in vivo activity of the ftuFabI inhibitors is attributed, at least in part, to the fact that these compounds are slow onset inhibitors with increased residence time on the enzyme. Based on this knowledge, a second series of mtbFabI inhibitors have been developed that incorporate modifications designed to reduce the entropic penalty for loop ordering and enzyme inhibition. The results of these studies will be presented.
 

Fatty Acid Synthase Inhibitors as Anticancer, Antibacterial and Antiparasitic Agents
9:00 AM-11:30 AM, Thursday, April 10, 2008 Morial Convention Center -- La Nouvelle, Blrm. A/B, Oral

Division of Medicinal Chemistry

The 235th ACS National Meeting, New Orleans, LA, April 6-10, 2008