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Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents

Sanjay S Khandekar1, Robert A Daines, John T Lonsdale

  • 1Protein Biochemistry, Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. Sanjay_Khandekar-1@gsk.com

Current Protein & Peptide Science
|February 7, 2003
PubMed

Insights

Novel broad-spectrum antibacterial agents are needed due to rising bacterial drug resistance. Targeting bacterial fatty acid synthesis (FAS) enzymes, particularly beta-ketoacyl-ACP synthases (KAS), offers a promising strategy for developing new antimicrobial drugs.

Area of Science:

  • Microbiology
  • Biochemistry
  • Drug Discovery

Background:

  • Increasing antibiotic resistance in pathogenic bacteria necessitates novel broad-spectrum antibacterial agents.
  • Fatty acid synthesis (FAS) is essential for bacterial survival, making its enzymes attractive antimicrobial targets.
  • Bacterial beta-ketoacyl-acyl carrier protein (ACP) synthases (KAS) are crucial for FAS initiation and regulation.

Purpose of the Study:

  • To review the biochemical, biophysical, and inhibition properties of bacterial KAS.
  • To highlight KAS as a key target for developing new antibacterial drugs.
  • To explore strategies for discovering potent, broad-spectrum antibacterial agents.

Main Methods:

  • Cloning, expression, and purification of KAS from various bacterial species.
  • Enzymological, structural, and screening studies of KAS.
  • Application of combinatorial chemistry, high-throughput screening, and rational drug design.

Main Results:

  • KAS enzymes are central to bacterial fatty acid synthesis.
  • Purified KAS enables detailed enzymological and structural investigations.
  • Multiple techniques facilitate the discovery of KAS inhibitors.

Conclusions:

  • Targeting bacterial KAS is a viable strategy for developing novel broad-spectrum antibiotics.
  • Integrated approaches combining structural biology and screening are key to drug discovery.
  • Further research into KAS properties will accelerate the development of urgently needed antibacterial agents.

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