<unk>  has shown good activity against a panel of Gram-positive bacteria, including various resistant strains.<unk>  works by inhibiting beta-ketoacyl synthases I/II (FabF/B), which are involved in the production of fatty acids required for bacterial cell membranes. It interferes with enzymes involved in the condensation steps in fatty acid biosynthesis, which Gram-positive bacteria need to biosynthesise cell membranes. Other enzymes in this pathway have similarly been proven as antibiotic targets, such as FabI, the enoyl-ACP (acyl carrier protein) reductase, which is inhibited by isoniazid and related compounds and the antiseptic agent triclosan. One proposed mechanism of action is that, firstly, the thiol group of FabF Cys163 is activated through the dipole moment of helix N-alpha-3 which lowers the pKa. The nucleophilicity of the cysteine is enhanced by an oxyanion hole formed with the backbone amides of Cys163 and Phe400. The crystal structure complex with<unk>  employed a C163Q mutant, which gave a 50-fold increase in apparent binding. The Gln163 residue lies adjacent to the carboxylate of<unk>  but makes no specific hydrogen bond. The close proximity of the carboxylate of<unk>  (presumed to be an anion) to the anionic thiol of Cys163 in the wild type enzyme may suggest the reason behind the increase in binding of the C163Q mutant. The second set of residues worth considering comprises His303 and His340, which play a role in the decarboxylation mechanism of the malonyl moiety. In particular, His303 activates a structured water to attack the carboxylate of the incoming malonyl-ACP. The crystal structure of FabF also demonstrates that His340 forms a hydrogen bond between the amide nitrogen of Leu342 and the N-delta- atom of the imidazole ring meaning that the lone pair must reside on this atom. In the<unk>  crystal structure the structured water adjacent to His303 is no longer present which may suggest an alternative electronic state for this residue. A strong possibility exists that His303 would present itself as a cation capable of forming an ionic interaction with the benzoic acid group of<unk> .
Platensimycin
Milbemycin
Diacerein
Ajulemic acid
Pingyangmycin
Simmondsin
Ascaricide
Griseofulvin