ABSTRACT
Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
Subject(s)
Acrylamides/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Fatty Acid Synthases/antagonists & inhibitors , Indoles/chemical synthesis , Naphthyridines/chemical synthesis , Oxidoreductases/antagonists & inhibitors , Abscess/drug therapy , Acrylamides/chemistry , Acrylamides/pharmacology , Administration, Oral , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Drug Resistance, Bacterial , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) , Enterococcus faecalis/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haemophilus influenzae/drug effects , Indoles/chemistry , Indoles/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Naphthyridines/chemistry , Naphthyridines/pharmacology , Rats , Staphylococcus aureus/drug effects , Stereoisomerism , Structure-Activity Relationship , Triclosan/pharmacologyABSTRACT
Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.
Subject(s)
Acrylamides/chemical synthesis , Aminopyridines/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Fatty Acid Synthases/antagonists & inhibitors , Oxidoreductases/antagonists & inhibitors , Acrylamides/chemistry , Acrylamides/pharmacology , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Databases, Factual , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fatty Acid Synthases/chemistry , Haemophilus influenzae/drug effects , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Models, Molecular , Oxidoreductases/chemistry , Rats , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Phenylbutyrates/pharmacology , Phenylbutyrates/pharmacokinetics , Acetates/chemistry , Administration, Oral , Aminopyridines/chemistry , Animals , Biological Availability , Cell Adhesion/drug effects , Cell Line , Half-Life , Humans , Phenylbutyrates/chemistry , RatsABSTRACT
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.