Mycolic acids are the major
lipid components of the unique mycobacterial cell wall responsible for the protection of the
tuberculosis bacilli from many outside threats.
Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as
trehalose- containing
glycolipids before being esterified to the
arabinogalactan portion of the cell wall and outer membrane
glycolipids. The large size of these unique
fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these
lipids to the mycobacterial cellular survival. There are many key
enzymes involved in the
mycolic acid biosynthetic pathway, including
fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC),
mycolic acid modifying
enzymes (SAM-dependent
methyltransferases, aNAT),
fatty acid activating and condensing
enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential
drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target
enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of
tuberculosis drug discovery, several of which show great promise as selective
tuberculosis therapeutics.