Structure-Assisted Discovery of an Aminothiazole Derivative as a Lead Molecule for Inhibition of Bacterial Fatty-Acid Synthesis.

摘要: Fatty-acid synthesis in bacteria is of great interest as a target for the discovery antibacterial compounds. The addition new acetyl moiety to growing fatty-acid chain, an essential step this process, catalyzed by β-ketoacyl-ACP synthase (KAS). It inhibited natural antibiotics such cerulenin and thiolactomycin; however, these lack requirements optimal drug development. Structure-based biophysical screening revealed novel synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds Escherichia coli KAS I with binding constant 25 µM determined fluorescence titration. A 1.35 A crystal structure its complex reveals noncovalent interactions active-site Cys163 hydrophobic residues pocket. active site accessible through open conformation Phe392 side chain no conformational changes are induced at upon ligand binding. This represents mode differs from thiolactomycin or interaction. structural information on protein–ligand interaction offers strategies further optimization low-molecular-weight compound.