title: Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
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.
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, Pennsylvania 19426, USA. Mark_A_Seefeld@gsk.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seefeld
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newlander
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Burgess
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Elkins
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Dalia R
authors.initials: DR
authors.lastname: Jakas
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Paul M
authors.initials: PM
authors.lastname: Keller
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Moore
authors.forename: David J
authors.initials: DJ
authors.lastname: Payne
authors.forename: Stewart
authors.initials: S
authors.lastname: Pearson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Polizzi
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Rittenhouse
authors.forename: Irene N
authors.initials: IN
authors.lastname: Uzinskas
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
authors.forename: William F
authors.initials: WF
authors.lastname: Huffman
mesh_terms: D000038:Abscess / Q000188:drug therapy; D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006193:Haemophilus influenzae / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000494:pharmacology
chemical_list: D000178:Acrylamides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C474145:N-methyl-N-(2-methyl-1H-indol-3ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide; D009287:Naphthyridines; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D064429:Fatty Acid Synthases