Lipid biosynthesis as a target for antibacterial agents.
Fatty acid biosynthesis, the first stage in membrane lipid biogenesis, is catalyzed in most bacteria by a series of small, soluble proteins that are each encoded by a discrete gene (Fig. 1; Table 1). This arrangement is termed the type II fatty acid synthase (FAS) system and contrasts sharply with the type I FAS of eukaryotes which is a dimer of a single large, multifunctional polypeptide. Thus, the bacterial pathway offers several unique sites for selective inhibition by chemotherapeutic agents. The site of action of isoniazid, used in the treatment of tuberculosis for 50 years, and the consumer antimicrobial agent triclosan were revealed recently to be the enoyl-ACP reductase of the type II FAS. The fungal metabolites, cerulenin and thiolactomycin, target the condensing enzymes of the bacterial pathway while the dehydratase/isomerase is inhibited by a synthetic acetylenic substrate analogue. Transfer of fatty acids to the membrane has also been inhibited via interference with the first acyltransferase step, while a new class of drugs targets lipid A synthesis. This review will summarize the data generated on these inhibitors to date, and examine where additional efforts will be required to develop new chemotherapeutics to help combat microbial infections.
Heath
R J
RJ
Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, Tennessee 38105, Memphis, USA. richard.heath@stjude.org
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D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000235:genetics / Q000378:metabolism*; D001424:Bacterial Infections / Q000188:drug therapy; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D003890:Desiccation; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004926:Escherichia coli / Q000235:genetics; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008050:Lipid A / Q000096:biosynthesis; D008055:Lipids / Q000096:biosynthesis*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000096:biosynthesis; D011487:Protein Conformation; D016415:Sequence Alignment; D013296:Streptococcus pneumoniae / Q000235:genetics
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D008050:Lipid A; D008055:Lipids; D010743:Phospholipids; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase