Identification of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase

Abstract

The FabI-related enoyl-ACP reductase enzymes of bacteria meet many of the criteria for antibacterial targets. These enzymes are essential for the growth of several pathogenic species, have no significant mammalian homologs, catalyze a rate-limiting step in a vital macromolecular biosynthetic pathway, and are already the targets of antibacterials used in the clinic (isoniazid) and in consumer products (triclosan). The suitability of FabI as an antibiotic target is diminished somewhat by the discovery that many pathogens carry an alternate unrelated enoyl-ACP reductase (FabK) or both reductases. However, a key human pathogen, Staphylococcus aureus and its increasingly common drug-resistant derivative MRSA are sensitive to FabI inhibitors. Screening for inhibitors of this target has resulted in the identification of five chemical classes of potent inhibitors. In addition, analogs of triclosan with increased potency and with pro-drug features have been engineered. At least one of these classes of inhibitors has been optimized and tested in animals for pharmacokinetic properties and efficacy. Further development of one or more of these classes and further screening are expected to generate new FabI inhibitors for application in the clinic against drug-resistant S. aureus.

Investigational Antimicrobial Agents of 2013

“…Like for the PDF inhibitors, no drug targeting fatty acid biosynthesis has been developed into an approved antibacterial drug outside the mycobacterial arena, although several research groups have conducted screening campaigns using this as a target (207)(208)(209)(210)(211). At GSK, lead compounds were identified from HTS assays for two enzymes involved in fatty acid biosynthesis: FabH, the ␤-ketoacyl-acyl carrier protein synthase III, and the enoyl-acyl carrier protein (ACP) reductase FabI (202).…”

Antibacterial targets in fatty acid biosynthesis

“…The enoyl-acyl-ACP reductase, FabI, continues to attract attention as a target in the FASII pathway, to some extent due to its proven susceptibility to isoniazid and triclosan [21]. However, enthusiasm for development of inhibitors of FabI is somewhat tempered by the existence of a structurally and mechanistically unrelated enzyme, FabK, that can catalyze the same reaction as FabI in some important pathogens [22].…”

Insilico Analysis of Phytoconstituents from Allium sativum as Potential Inhibitors of Inha in Mycobacterium tuberculosis

“…The rate limiting step and final step Mycobacterium Enoyl-ACP reductase catalyzes the final step and rate limiting step in the fatty acid synthesis (mycolic acid) by utilizing NADH to reduce trans double bond of longer fatty acyl substrates (Moir DT, 2005, Rozwarski DA, et al, 1998 and are validated as the excellent target for drug development against M.tuberculosis (Yamada H, et al, 1995). The replacement of an amino acid in the NADH binding site of InhA apparently results in INH resistance, preventing the inhibition of mycolic acid biosynthesis (Zhang YM, et al, 2006).…”