# Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs
## 2 The Mycobacterial Cell Wall  
The biosynthesis of the mycobacterial cell wall components has been extensively described recently [20, 21, 22], and only a summary of the most pertinent points for this article is presented here. The proteins implicated or targeted by TB drugs discussed below are underlined. The three main components of the cell wall are the peptidoglycan (PG), the lipopolysaccharidesaccharides (arabinogalactan, lipoarabinomannan, and lipomannan) and the outer membrane, which contains mycolic acids, various glycolipids and phthiocerod dimycoreosides (Figure 1). The _M. tuberculosis_ peptidoglycan can is located outside of the mycobacterial inner membrane, conferring rigidity, integrity and shape to the cell [22]. The peptidoglycan is a polysaccharide composed of alternating _N_-acetylglucosamine and muramic acid (either _N_-acetylated or _N_-glycosylated) residues linked by \(\beta\) (1\(\rightarrow\)4) bonds [23, 24, 25, 26]. Strands of polysaccharides are acylated on the muramic acid residues by the pentapeptide L-alanyl-D-isoglutamyl-_meso_-diaminophenyl-D-alanyl-D-alanine synthesized by the Mur ligases (MurC/D/E/F). The acylation reaction is performed by the D-Ala:D-Ala ligase DdIA. The pentapeptides are cross-linked to form the peptidoglycan. Two types of cross-linkages are observed in _M. tuberculosis_: (i) the D,D-transeptidase activity of the penicillin binding proteins PonA1 and PonA2 cross-links meso-diaminopimelic acid and D-alanine to form a 3\(\rightarrow\)4 linkage; (ii) the L,D-transpeptidatases (LdtMt1 to 5) cross-link two meso-diaminopimelate residues to form a 3\(\rightarrow\)3 linkage [22]. The arabinolactan is a branched polysaccharide composed of arabin (Araf) and galactose (Galf) residues in the furanose configuration [27]. The first step in the arabinolactan biosynthesis is the formation of the linker that anchors the arabinolactan complex to the peptidoglycan via the \(\mathbf{N}\)-glycolylated-muramic acid residues [28]. This linker is a decaprenyl-diphospho-\(\mathbf{N}\)-acetylglucosamine-rhammosyl molecule produced by the successive transfer of \(\mathbf{N}\)-acetylglucosamine-1-phosphate to decaprenyl-phosphate by WecA followed by the transfer of L-rhammose by WbbL. On this linker, 30 linear Gal/residues are added by the galactofuranosyltransferases GlTf1 and GlTf2. An Arafunit is then transferred to the galactan chain using the arabinose donor decaprenylphosphoryl-D-arabinose (DPA). DPA is formed through several steps, starting with phospho-\(\alpha\)-D-ribosyl-1-pyrophosphate (pRpp). UbiA adds a decaprenyl group to form decaprenol-1-monophosphate 5-phosphorose (DPPR), which is dephosphorylated and epimerized by DprE1 and DprE2 to form DPA. The arabinofuranosyltransferase AftA catalyzes the transfer of the first unit of Araf to the galactan chain. The arabosyltransferaseranses EmbA and EmbB catalyze the further addition of Araf to form the arabinan. The final product, the arabininogalactan, is a linear galactan to which highly branched arabians are attached. The arabinan anchors the mycolic acids forming the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. Mycolic acids are the hallmark of the _M. tuberculosis_ cell wall, an essential component regulating the permeability, acid-fast staining, viability and virulence of _M. tuberculosis_[29]. As stated above,  
Figure 1: Illustration of the mycobacterial cell wall. The outermost layer of the cell wall, the capsule, is omitted. The cell wall components/sites inhibited by the tuberculosis (TB) drugs discussed herein are indicated. Abbreviations: AG, arabinolactan; LAM, lipoarabinomannan; LM, lipomannan; MA, mycolic acids; PG, peptidoglycan; P, phospholipid; PIMs, phosphatidyl-_myo_-inositol mannosides; INH, isoniaid; ETH, ethionamide; PTH, prothionamide; TAC, thiacetazone; PMD, pretomanid; EMB, ethambuttol.