New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics

Abstract

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.

Figure 1

Representative structures of mycolic acids [10-13].

Figure 2

Pictorial representation of key enzymes, transporters and transferases involved in the mycolic acid biosynthetic pathway. β-ketoacyl-ACP synthase A (KasA), β-ketoacyl-ACP synthase B (KasB), β-ketoacyl-ACP reductase (MabA), β-hydroxyacyl-ACP dehydratase (Had), enoyl-ACP reductase (InhA), trehalose monomycolate (TMM).

Figure 3

Structures of approved drugs that target the mycolic acid biosynthetic pathway.

Figure 4

Activation of INH by KatG and formation of the isonicotinyl-NAD complex, which is a non-covalent InhA inhibitor.

Figure 5

Representative ISO analogs and M. tb MIC values.

Figure 6

TAC analogs and MIC values.

Figure 7

Representation of current EthR inhibitors.

Figure 8

FAS-II cycle used by M. tb to elongate fatty acids in the synthesis of mycolic acids. β-ketoacyl-ACP synthase A (KasA), β-ketoacyl-ACP synthase B (KasB), β-ketoacyl-ACP reductase (MabA), β-hydroxyacyl-ACP dehydratases (HadAB and HadBC), enoyl-ACP reductase (InhA).

Figure 9

Representative structures of the Kas inhibitor thiolactomycin and its analogs.

Figure 10

Structure of the InhA inhibitor pyridomycin.

Figure 11

Structures of methyl transferase inhibitors.

Figure 12

Structures of aNAT triazole-based inhibitors and IC₅₀ values against P. aeruginosa aNAT [113].

Figure 13

Structures of aNAT pyrazole-based inhibitors and IC₅₀ values against P. aeruginosa aNAT [114].

Figure 14

Proposed mechanism for piperidinol suicide inhibitors [115].

Figure 15

Structures and IC₅₀ values of reported AccD5 inibitors [117].

Figure 16

Structures and MIC values for lead coumarin-based FadD32 inhibitors [118].

Figure 17

Structures and activity of thiophene-based Pks13 inhibitors [120].

Figure 18

Structures of MmpL3 inhibitors BM212, SQ109 and C215.

Figure 19

Representative structures and antitubercular data for GSK's MmpL3 inhibitors [137, 138].

Figure 20

Structures of phosphonate inhibitors of Ag85C [143].

Figure 21

Structure for the suicide inhibitor of Ag85 and plausible mechanism of action [144].

Figure 22

Anti-Ag85 thiophenyl and thiazole compounds implicated in altering the TDM and TMM balance.

Figure 23

Structure of glycoconjugate targeting the Ag85 complex.