Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents
Open Access
- 1 October 2002
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 46 (10), 3118-3124
- https://doi.org/10.1128/aac.46.10.3118-3124.2002
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-1 H -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.Keywords
This publication has 13 references indexed in Scilit:
- Discovery of Aminopyridine-Based Inhibitors of Bacterial Enoyl-ACP Reductase (FabI)Journal of Medicinal Chemistry, 2002
- Biochemical and genetic characterization of the action of triclosan on Staphylococcus aureus.Journal of Antimicrobial Chemotherapy, 2001
- Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discoveryDrug Discovery Today, 2001
- Identification and Characterization of Inhibitors of Multidrug Resistance Efflux Pumps in Pseudomonas aeruginosa : Novel Agents for Combination TherapyAntimicrobial Agents and Chemotherapy, 2001
- The millennium bugs — the need for and development of new antibacterialsInternational Journal of Antimicrobial Agents, 2000
- A triclosan-resistant bacterial enzymeNature, 2000
- Efficacy of High-Dose Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniaeAntimicrobial Agents and Chemotherapy, 1999
- A Mechanism of Drug Action Revealed by Structural Studies of Enoyl ReductaseScience, 1996
- The Enoyl‐[Acyl‐Carrier‐Protein] Reductase (FabI) of Escherichia coli, which Catalyzes a Key Regulatory Step in Fatty Acid Biosynthesis, Accepts NADH and NADPH as Cofactors and is Inhibited by Palmitoyl‐CoAEuropean Journal of Biochemistry, 1996
- Enoyl-Acyl Carrier Protein Reductase (fabI) Plays a Determinant Role in Completing Cycles of Fatty Acid Elongation in Escherichia coliJournal of Biological Chemistry, 1995