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.
Keywords: Tuberculosis, antituberculosis agents, mycolic acid, fatty acid synthase, KasA, KasB, MabA, HadABC, InhA, FadD32, Pks13,
MmpL3, antigen 85.
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