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

@article{citeulike:2754886, 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. 10.1128/AAC.46.10.3118-3124.2002}, author = {Payne, David J. and Miller, William H. and Berry, Valerie and Brosky, John and Burgess, Walter J. and Chen, Emile and Dewolf, Walter E. and Fosberry, Andrew P. and Greenwood, Rebecca and Head, Martha S. and Heerding, Dirk A. and Janson, Cheryl A. and Jaworski, Deborah D. and Keller, Paul M. and Manley, Peter J. and Moore, Terrance D. and Newlander, Kenneth A. and Pearson, Stewart and Polizzi, Brian J. and Qiu, Xiayang and Rittenhouse, Stephen F. and Slater-Radosti, Courtney and Salyers, Kevin L. and Seefeld, Mark A. and Smyth, Martin G. and Takata, Dennis T. and Uzinskas, Irene N. and Vaidya, Kalindi and Wallis, Nicola G. and Winram, Scott B. and Yuan, Catherine C. and Huffman, William F. }, citeulike-article-id = {2754886}, doi = {10.1128/AAC.46.10.3118-3124.2002}, journal = {Antimicrob. Agents Chemother.}, keywords = {antibiotics}, month = {October}, number = {10}, pages = {3118--3124}, posted-at = {2008-05-05 03:21:21}, priority = {2}, title = {Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents}, url = {http://dx.doi.org/10.1128/AAC.46.10.3118-3124.2002}, volume = {46}, year = {2002} }

TY - JOUR ID - citeulike:2754886 L3 - citeulike-article-id:2754886 TI - Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents JF - Antimicrob. Agents Chemother. VL - 46 IS - 10 SP - 3118 EP - 3124 N2 - 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. 10.1128/AAC.46.10.3118-3124.2002 KW - antibiotics AU - Payne, David AU - Miller, William AU - Berry, Valerie AU - Brosky, John AU - Burgess, Walter AU - Chen, Emile AU - Dewolf, Walter AU - Fosberry, Andrew AU - Greenwood, Rebecca AU - Head, Martha AU - Heerding, Dirk AU - Janson, Cheryl AU - Jaworski, Deborah AU - Keller, Paul AU - Manley, Peter AU - Moore, Terrance AU - Newlander, Kenneth AU - Pearson, Stewart AU - Polizzi, Brian AU - Qiu, Xiayang AU - Rittenhouse, Stephen AU - Slater-Radosti, Courtney AU - Salyers, Kevin AU - Seefeld, Mark AU - Smyth, Martin AU - Takata, Dennis AU - Uzinskas, Irene AU - Vaidya, Kalindi AU - Wallis, Nicola AU - Winram, Scott AU - Yuan, Catherine AU - Huffman, William PY - 2002/10/01/ UR - http://dx.doi.org/10.1128/AAC.46.10.3118-3124.2002 ER -