1MFP

E. coli Enoyl Reductase in complex with NAD and SB611113

Summary for 1MFP

• Entry DOI: 10.2210/pdb1mfp/pdb
• Related: 1C14 1I2Z 1I30
• Descriptor: enoyl-[acyl-carrier-protein] reductase [Nadh], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (E)-N-METHYL-N-(1-METHYL-1H-INDOL-3-YLMETHYL)-3-(7-OXO-5,6,7,8-TETRAHYDRO-[1,8]NAPHTHYRIDIN-3-YL)-ACRYLAMIDE, ... (5 entities in total)
• Functional Keywords: fabi, enoyl reductase, enoyl-acp reductase, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 57957.64

Authors

Seefeld, M.A.,Miller, W.H.,Newlander, K.A.,Burgess, W.J.,DeWolf Jr., W.E.,Elkins, P.A.,Head, M.S.,Jakas, D.R.,Janson, C.A.,Keller, P.M.,Manley, P.J.,Moore, T.D.,Payne, D.J.,Pearson, S.,Polizzi, B.J.,Qiu, X.,Rittenhouse, S.F.,Uzinskas, I.N.,Wallis, N.G.,Huffman, W.F. (deposition date: 2002-08-13, release date: 2003-05-06, Last modification date: 2024-02-14)

Primary citation

Seefeld, M.A.,Miller, W.H.,Newlander, K.A.,Burgess, W.J.,DeWolf Jr., W.E.,Elkins, P.A.,Head, M.S.,Jakas, D.R.,Janson, C.A.,Keller, P.M.,Manley, P.J.,Moore, T.D.,Payne, D.J.,Pearson, S.,Polizzi, B.J.,Qiu, X.,Rittenhouse, S.F.,Uzinskas, I.N.,Wallis, N.G.,Huffman, W.F.
Indole Naphthyridinones as Inhibitors of Bacterial Enoyl-ACP Reductases FabI and FabK
J.MED.CHEM., 46:1627-1635, 2003

PubMed Abstract: Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.

PubMed: 12699381
DOI: 10.1021/jm0204035

Experimental method

X-RAY DIFFRACTION (2.33 Å)