Synthesis and recycling of the mycobacterial cell envelope

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis, is a recognised global health concern. The efficacy of the current treatment regime is under threat due to the emergence of antibiotic resistance, directing an urgent requirement for the discovery of new anti-tubercular agents and drug targets. The mycobacterial cell wall is a well-validated drug target for Mtb and is composed of three adaptive macromolecular structures, peptidoglycan, arabinogalactan and mycolic acids, an array of complex lipids and carbohydrates. The majority of the enzymes involved in cell wall synthesis have been established, whilst studies directed towards the mechanisms of remodelling and recycling have been neglected. This review briefly describes mycobacterial cell wall synthesis, and focuses on aspects of remodelling and recycling, thus highlighting opportunities for future research.

Graphical abstract

Figure 1

Mycobacterial cell wall architecture. A schematic representation of the mycobacterial cell wall, highlighting the key features. Abbreviations: mycobacterial inner membrane (MIM), mycobacterial outer membrane (MOM), phosphatidyl-myo-inositol mannosides, (PIMs, with acylation sites Ac₁/Ac₂), lipomannan (LM), lipoarabinomannan (LAM), mannosylated lipoarabinomannan (ManLAM), diacyl-trehalose (DAT), polyacyl-trehalose (PAT), phthiocerol dimycocerosate (PDIM), and sulfoglycolipid (SGL). An outer membrane protein has been included (green) to depict how solutes traverse the hydrophobic layer.

Figure 2

Peptidoglycan biosynthesis, remodelling and recycling. Peptidoglycan biosynthesis has been reviewed in detail [7]. Enzymes involved in peptidoglycan synthesis (no symbol), remodelling (*) and recycling (**) are shown in bold type. Question marks (?) indicate a predicted enzyme function.

Figure 3

Arabinogalactan, PIMs, LM, LAM and ManLAM biosynthesis and remodelling. (a) The synthesis of arabinogalactan and (b) synthesis of the glycolipids, PIMs, LM, LAM and ManLAM. Arabinogalactan and glycolipid biosynthesis are the subjects of a recent comprehensive review [3]. Abbreviations: phospho-α-d-ribosyl-1-pyrophosphate (pRpp), decaprenol-1-monophosphate 5-phosphoribose (DPPR), decaprenol-1-phosphoribose (DPR), decaprenylphosphoryl-d-arabinose (DPA), d-arabinose in furanose ring form (d-Araf), d-galactose in furanose ring form (d-Galf), l-rhamnose in pyranose ring form (l-Rhap), d-mannose in pyranose ring form (d-Manp), phosphatidyl-myo-inositol mannosides, (PIMs, with acylation sites Ac₁/Ac₂).

Figure 4

Mycolic acid biosynthesis and recycling. Intermediate chain-length fatty acids and mycolic acids can be recycled through the β-oxidation pathway and trehalose taken up and used directly in the synthesis of TMM/TDM (trehalose monomycolate/dimycolate). The synthesis of mycolic acids has been described in a detailed review [39].