Antibacterial targets in fatty acid biosynthesis

Abstract

The fatty acid biosynthesis pathway is an attractive but still largely unexploited target for the development of new antibacterial agents. The extended use of the antituberculosis drug isoniazid and the antiseptic triclosan, which are inhibitors of fatty acid biosynthesis, validates this pathway as a target for antibacterial development. Differences in subcellular organization of the bacterial and eukaryotic multienzyme fatty acid synthase systems offer the prospect of inhibitors with host versus target specificity. Platensimycin, platencin, and phomallenic acids, newly discovered natural product inhibitors of the condensation steps in fatty acid biosynthesis, represent new classes of compounds with antibiotic potential. An almost complete catalog of crystal structures for the enzymes of the type II fatty acid biosynthesis pathway can now be exploited in the rational design of new inhibitors, as well as the recently published crystal structures of type I FAS complexes.

Figure 1. Scheme for the type II FAS reaction pathway

Enzyme names are in red and cyan, the latter indicating enzymes for which inhibitors exist.

Figure 2

Structures of natural product (A) and chemically synthesized (B) type II FAS inhibitors (see text for more details).

Figure 3. Platensimycin in the active site of FabF

The carboxylate of platensimycin lies in the malonate binding site (H303, H340) coplanar with the sidechain of Q163, which substitutes for C163 and simulates an acyl-linked sidechain.