Bacterial β-ketoacyl-Acyl Carrier Protein Synthases as Targets for Antibacterial Agents

Sanjay   S.   Khandekar; Robert   A.   Daines; John   T.   Lonsdale

Abstract

As a result of increasing drug resistance in pathogenic bacteria, there is a critical need for novel broad-spectrum antibacterial agents. As fatty acid synthesis (FAS) in bacteria is an essential process for cell survival, the enzymes involved in the FAS pathway have emerged as promising targets for antimicrobial agents. Several lines of evidence have indicated that bacterial condensing enzymes are central to the initiation and elongation steps in bacterial fatty acid synthesis and play a pivotal role in the regulation of the entire fatty acid synthesis pathway. β-ketoacyl-acyl carrier protein (ACP) synthases (KAS) from various bacterial species have been cloned, expressed and purified in large quantities for detailed enzymological, structural and screening studies. Availability of purified KAS from a variety of bacteria, along with a combination of techniques, including combinatorial chemistry, high-throughput screening, and rational drug design based on crystal structures, will undoubtedly aid in the discovery and development of much needed potent and broadspectrum antibacterial agents. In this review we summarize the biochemical, biophysical and inhibition properties of β-ketoacyl-ACP synthases from a variety of bacterial species.

Keywords: ketoacyl-acyl carrier protein, acp, kas, acp synthase, type1 fatty acid synthesis, fas, type1 fas

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