1. Discovery of a novel and potent class of FabI-directed antibacterial agents.
- Author
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Payne DJ, Miller WH, Berry V, Brosky J, Burgess WJ, Chen E, DeWolf WE Jr, Fosberry AP, Greenwood R, Head MS, Heerding DA, Janson CA, Jaworski DD, Keller PM, Manley PJ, Moore TD, Newlander KA, Pearson S, Polizzi BJ, Qiu X, Rittenhouse SF, Slater-Radosti C, Salyers KL, Seefeld MA, Smyth MG, Takata DT, Uzinskas IN, Vaidya K, Wallis NG, Winram SB, Yuan CC, and Huffman WF
- Subjects
- Animals, Drug Resistance, Multiple, Bacterial, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), Gram-Negative Bacteria drug effects, Gram-Negative Bacteria enzymology, Humans, Male, Microbial Sensitivity Tests, Rats, Rats, Sprague-Dawley, Staphylococcal Infections drug therapy, Staphylococcus aureus drug effects, Staphylococcus aureus enzymology, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae enzymology, Structure-Activity Relationship, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Oxidoreductases antagonists & inhibitors
- 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.
- Published
- 2002
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