Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role inMycobacterium tuberculosisphysiology and host–pathogen interaction

Abstract

Approximately one third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. This bacterium has an unusual lipid-rich cell wall containing a vast repertoire of antigens, providing a hydrophobic impermeable barrier against chemical drugs, thus representing an attractive target for vaccine and drug development. Apart from the mycolyl–arabinogalactan–peptidoglycan complex, mycobacteria possess several immunomodulatory constituents, notably lipomannan and lipoarabinomannan. The availability of whole-genome sequences of M. tuberculosis and related bacilli over the past decade has led to the identification and functional characterization of various enzymes and the potential drug targets involved in the biosynthesis of these glycoconjugates. Both lipomannan and lipoarabinomannan possess highly variable chemical structures, which interact with different receptors of the immune system during host–pathogen interactions, such as Toll-like receptors-2 and C-type lectins. Recently, the availability of mutants defective in the synthesis of these glycoconjugates in mycobacteria and the closely related bacterium, Corynebacterium glutamicum, has paved the way for host–pathogen interaction studies, as well as, providing attenuated strains of mycobacteria for the development of new vaccine candidates. This review provides a comprehensive account of the structure, biosynthesis and immunomodulatory properties of these important glycoconjugates.

Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides

“…We note that in addition to the early intermediates Ac 1 /Ac 2 PIM 2 , the extensively mannosylated forms Ac 1 /Ac 2 PIM 6 were also found predominantly in the IM, confirming the pathway proposed by Besra and coworkers (25). It is also important that TMM was exclusively found in the IM, but TDM only in the OM (Table 1).…”

“…Interestingly, enzymes involved in the synthesis of polar PIMs are reported to reside in a special subdomain of IM, with a strong interaction with the rest of the envelope (11). According to the proposed biosynthetic pathway (25), these lipids should be present mostly in the inner leaflet (of the IM), which is thus expected to be composed almost entirely of these compounds (Fig. 5).…”

Structural Differences in Lipomannans from Pathogenic and Nonpathogenic Mycobacteria That Impact CD1b-restricted T Cell Responses

“…In this context, several studies using mycobacterial lipoglycans support the importance of the hydrophilic domain in T cell recognition (4,7). This is the case for ManLAM and LM, where the structural complexity of their hydrophilic domain, defined as a rigid, linear, and, in some cases, large structure with multiple branches (34), allows us to speculate on additional factors (i.e. charge) to stabilize them within the CD1 groove for Ag presentation.…”

The synthesis and biological evaluation of mycobacterial p-hydroxybenzoic acid derivatives (p-HBADs)

“…[5][6][7][8][9][10] Glycosyl processing enzymes are essential for bacterial cell wall biosynthesis and many of the key components of the cell wall display complex carbohydrates. 11,12 The critical and diverse biological functions of these glycans in the life-cycle of the mycobacterium are only beginning to be understood. Phenolic glycolipids (PGLs) are a family of bacterial glycolipids with a lipid core similar to dimycocerosates of phthiocerol (DIMs).…”