Lipid biosynthesis as a target for antibacterial agents

Fatty acid biosynthesis, the first stage in membrane lipid biogenesis, is c atalyzed in most bacteria by a series of small, soluble proteins that are e ach encoded by a discrete gene (Fig. 1; Table 1). This arrangement is terme d the type II fatty acid synthase (FAS) system and contrasts sharply with t he type I FAS of eukaryotes which is a dimer of a single large, multifuncti onal polypeptide. Thus, the bacterial pathway offers several unique sites f or selective inhibition by chemotherapeutic agents. The site of action of i soniazid, used in the treatment of tuberculosis for 50 years, and the consu mer antimicrobial agent triclosan were revealed recently to be the enoyl-AC P reductase of the type II FAS. The fungal metabolites, cerulenin and thiol actomycin, target the condensing enzymes of the bacterial pathway while the dehydratase/isomerase is inhibited by a synthetic acetylenic substrate ana logue. Transfer of fatty acids to the membrane has also been inhibited via interference with the first acyltransferase step, while a new class of drug s targets lipid A synthesis. This review will summarize the data generated on these inhibitors to date, and examine where additional efforts will be r equired to develop new chemo therapeutics to help combat microbial infectio ns. (C) 2001 Elsevier Science Ltd. All rights reserved.