Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis

Much of the early structural definition of the cell wall of Mycobacterium spp. was initiated in the 1960s and 1970s. There was a long period of inactivity, but more recent developments in NMR and mass spectral analysis and definition of the M. tuberculosis genome have resulted in a thorough understanding, not only of the structure of the mycobacterial cell wall and its lipids but also the basic genetics and biosynthesis. Our understanding nowadays of cell-wall architecture amounts to a massive "core" comprised of peptidoglycan covalently attached via a linker unit (L-Rha-D-GlcNAc-P) to a linear galactofuran, in turn attached to several strands of a highly branched arabinofuran, in turn attached to mycolic acids. The mycolic acids are oriented perpendicular to the plane of the membrane and provide a truly special lipid barrier responsible for many of the physiological and disease-inducing aspects of M. tuberculosis. Intercalated within this lipid environment are the lipids that have intrigued researchers for over five decades: the phthiocerol dimycocerosate, cord factor/dimycolyltrehalose, the sulfolipids, the phosphatidylinositol mannosides, etc. Knowledge of their roles in "signaling" events, in pathogenesis, and in the immune response is now emerging, sometimes piecemeal and sometimes in an organized fashion. Some of the more intriguing observations are those demonstrating that mycolic acids are recognized by CD1-restricted T-cells, that antigen 85, one of the most powerful protective antigens of M. tuberculosis, is a mycolyltransferase, and that lipoarabinomannan (LAM), when "capped" with short mannose oligosaccharides, is involved in phagocytosis of M. tuberculosis. Definition of the genome of M. tuberculosis has greatly aided efforts to define the biosynthetic pathways for all of these exotic molecules: the mycolic acids, the mycocerosates, phthiocerol, LAM, and the polyprenyl phosphates. For example, we know that synthesis of the entire core is initiated on a decaprenyl-P with synthesis of the linker unit, and then there is concomitant extension of the galactan and arabinan chains while this intermediate is transported through the cytoplasmic membrane. The final steps in these events, the attachment of mycolic acids and ligation to peptidoglycan, await definition and will prove to be excellent targets for a new generation of anti-tuberculosis drugs.