1LX6

Crystal Structure of E. Coli Enoyl Reductase-NAD+ with a Bound Benzamide Inhibitor

Summary for 1LX6

• Entry DOI: 10.2210/pdb1lx6/pdb
• Related: 1C14 1I2Z 1I30 1lxc 1QG6
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-[(ACETYL-METHYL-AMINO)-METHYL]-4-AMINO-N-METHYL-N-(1-METHYL-1H-INDOL-2-YLMETHYL)-BENZAMIDE, ... (4 entities in total)
• Functional Keywords: fabi, enoyl reductase, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 57869.64

Authors

Smith, W.W.,Qiu, X.,Janson, C.A. (deposition date: 2002-06-04, release date: 2002-09-04, Last modification date: 2024-02-14)

Primary citation

Miller, W.H.,Seefeld, M.A.,Newlander, K.A.,Uzinskas, I.N.,Burgess, W.J.,Heerding, D.A.,Yuan, C.C.,Head, M.S.,Payne, D.J.,Rittenhouse, S.F.,Moore, T.D.,Pearson, S.C.,Berry, V.,DeWolf Jr., W.E.,Keller, P.M.,Polizzi, B.J.,Qiu, X.,Janson, C.A.,Huffman, W.F.
Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).
J.Med.Chem., 45:3246-3256, 2002

PubMed Abstract: Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.

PubMed: 12109908
DOI: 10.1021/jm020050+

Experimental method

X-RAY DIFFRACTION (2.4 Å)