title: Discovery of a novel and potent class of FabI-directed antibacterial agents.
abstract: Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
authors.affiliation: Microbial, Musculoskeletal and Proliferative Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA. David_J_Payne@gsk.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Payne
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Valerie
authors.initials: V
authors.lastname: Berry
authors.forename: John
authors.initials: J
authors.lastname: Brosky
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Burgess
authors.forename: Emile
authors.initials: E
authors.lastname: Chen
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fosberry
authors.forename: Rebecca
authors.initials: R
authors.lastname: Greenwood
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Jaworski
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: Kenneth A
authors.initials: KA
authors.lastname: Newlander
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: Courtney
authors.initials: C
authors.lastname: Slater-Radosti
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Salyers
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seefeld
authors.forename: Martin G
authors.initials: MG
authors.lastname: Smyth
authors.forename: Dennis T
authors.initials: DT
authors.lastname: Takata
authors.forename: Irene N
authors.initials: IN
authors.lastname: Uzinskas
authors.forename: Kalindi
authors.initials: K
authors.lastname: Vaidya
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
authors.forename: Scott B
authors.initials: SB
authors.lastname: Winram
authors.forename: Catherine C K
authors.initials: CC
authors.lastname: Yuan
authors.forename: William F
authors.initials: WF
authors.lastname: Huffman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)