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Antimicrobial Agents and Chemotherapy, October 2002, p. 3118-3124, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3118-3124.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

David J. Payne,1* William H. Miller,1 Valerie Berry,1 John Brosky,1 Walter J. Burgess,1 Emile Chen,2 Walter E. DeWolf Jr.,1 Andrew P. Fosberry,3 Rebecca Greenwood,1 Martha S. Head,4 Dirk A. Heerding,1 Cheryl A. Janson,4 Deborah D. Jaworski,1 Paul M. Keller,5 Peter J. Manley,1 Terrance D. Moore,1 Kenneth A. Newlander,1 Stewart Pearson,1 Brian J. Polizzi,5 Xiayang Qiu,4 Stephen F. Rittenhouse,1 Courtney Slater-Radosti,1 Kevin L. Salyers,2 Mark A. Seefeld,1 Martin G. Smyth,3 Dennis T. Takata,1 Irene N. Uzinskas,1 Kalindi Vaidya,6 Nicola G. Wallis,1,{dagger} Scott B. Winram,1 Catherine C. K. Yuan,1 and William F. Huffman7

Microbial, Musculoskeletal and Proliferative Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426,1 Drug Metabolism and Pharmacokinetics,2 Computational and Structural Sciences,4 Assay Methodology and Development,5 Molecular Screening,6 Cancer and Cardiovascular and Urogenital Diseases, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406,7 Gene Expression and Protein Biochemistry, GlaxoSmithKline Pharmaceuticals, Harlow CM19 5AW, United Kingdom3

Received 20 February 2002/ Returned for modification 2 May 2002/ Accepted 12 June 2002

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.

* Corresponding author. Mailing address: Antimicrobials and Host Defense (UP1345), GlaxoSmithKline, 1250 South Collegeville Rd., Collegeville, PA 19426-0989. Phone: (610) 917-7355. Fax: (610) 917-7901. E-mail: David_J_Payne{at}gsk.com.

{dagger} Present address: Astex-Technology, Cambridge CB4 0WE, United Kingdom.

Antimicrobial Agents and Chemotherapy, October 2002, p. 3118-3124, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3118-3124.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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