New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

Abstract

Mycolic acids are the major lipid component 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.

The Mycobacterial Cell Envelope--Lipids

“…4 and Table 1). A comprehensive review of these efforts was recently published by North et al (2013), and we will here only briefly describe some of the most exciting developments that have occurred in the last few years. Target-based screening uses biochemical and structural approaches to design, screen, and further evaluate a compound's activity against a specific molecular target.…”

Current perspectives in drug discovery against tuberculosis from natural products

“…As an outstanding scientist, Professor P. Sensi understood what research scientists in the field of TB drug discovery would realize many years later. Afterwards, a lot of compounds have been discovered that inhibit specific steps involved in either arabinogalactan or mycolic acid biosynthesis [28]. Novel efficacious and safe anti-TB drugs are currently needed so as: (1) to shorten the duration of TB therapy; (2) to be able to treat MDR, XDR and totally drug resistant (TDR) TB strains; (3) to be able to treat latent TB; (4) to be able to act in a synergistic manner with other co-administered anti-TB drugs; and, finally, (5) to be able to be safely co-administered with anti-HIV agents.…”

Mycobacterium tuberculosisRv1265 promotes mycobacterial intracellular survival and alters cytokine profile of the infected macrophage

“…North, Jackson, & Lee, 2014;Portevin et al, 2014). Whether the increased production of C26:0 is the result of boosted mycolic acid biosynthesis in Ms_Rv1265 remains to be determined.…”