Members of the
Precise structures of the lipid moieties displayed in members of the
2. Mycolic acids
The 70 to 90 carbon mycolic acids (MAs) are very characteristic chemical components in the genus
Recent physiochemical investigations have clearly demonstrated that mycolic acids characteristically adopt distinctly different folded conformations depending on structural niceties [20-24]. Ketomycolates in
3. Esters of mycolic acids
The so-called “cord factors” are the best known mycolic acid esters in mycobacteria; they are principally trehalose dimycolates (TDMs) with trehalose monomycolates (TMMs) also being encountered (Figure 3). The proportions of TDMs and TMMs vary widely in mycobacteria so an integral structural role is not indicated, their main importance lying in the key role as intermediates in the transfer of mycolic acids on to arabinosyl units in the cell envelope . Glucose monomycolates (GMMs) are common in mycobacteria, but in highly variable proportions . Consistent proportions, however, are recorded for monomycoloyl glycerols (MMGs) (Figure 3) in the
4. Phthiocerol and phenolphthiocerol dimycocerosate families
The phthiocerol and phenolphthiocerol long-chain diols are esterified by multimethyl-branched “mycocerosic” acids whose chiral centres have
The oligosaccharide substituents of PGLs have demonstrable antigenicity  but the individual sugar units are relatively hydrophobic. Certain members of the
5. Acyl trehaloses
In addition to TDMs and TMMs, there are families of trehalose-based glycolipids acylated with multimethyl branched fatty acids with
A highly polar series of lipids, which include trehalose in their saccharide core, are termed lipooligosaccharides (LOSs) [42,43]. Such lipids are absent in many modern
7. Phosphatidylinositol mannosides and other polar lipids
The mycobacterial plasma membrane incorporates conventional polar lipids, such as phosphatidylethanolamine (PE), phosphatidylinositol (PI) and diphosphatidylglycerol (DPG) (Figure 7), which can interact together to form the basis of a typical membrane bilayer. However, most mycobacteria have a remarkably consistent family of four phosphatidylinositol mannosides (PIMs); these comprise mono- (AcPIM2) and diacyl phosphatidylinositol dimannosides (Ac2PIM2) and mono- (AcPIM6) and diacyl phosphatidylinositol hexamannosides (Ac2PIM6) (Figure 7) [46-49]. Recent research has provided evidence that PIM2 and PIM6 classes may be unevenly distributed over the two leaflets of the mycobacterial plasma membrane . These findings will be interpreted, later, as showing that PIMs may act to reinforce the plasma membrane, perhaps adding a further level of selective permeability to the mycobacterial cell envelope.
8. Lipomannan and lipoarabinomannan
The basic structures of the PIMs polar lipid family (Figure 8) share the same manno-phosphatidylinositol (MPI) anchor with two classes of characteristic large lipoglycans, namely lipomannans (LMs) and lipoarabinomannans (LAMs) (Figure 8) [50-54].
9. Mycoloylarabinogalactan-peptidoglycan (mAGP)
The overall chemical structure of this complex macromolecule has been clarified during the past decade [55-58]. A specific linker unit covalently binds the proximal galactan portion of the arabinogalactan to peptidoglycan with the distal arabinose moieties providing anchorage for the 70 to 90 carbon long-chain mycolic acids (Figure 9) [19,55-58]. While chemical connectivity is established, conformational preferences of the carbohydrate domains remain a matter of conjecture with diverse interpretations. It is becoming evident that versatile peptidoglycans can adopt different conformational arrangements, depending on the length of the polymeric disaccharide chains with helices being possible for shorter units . It was shown that a synthetic peptidoglycan adopted a right-handed helical conformation . A distinctive feature of mycobacterial peptidoglycan is the presence of a proportion of
The proposed mAGP arrangement (Figure 10) is based on a “scaffold” model [61,62], where peptide cross-linked helices are interspersed with helices of the galactan part of the arabinogalactan; the arabinan portion is then arranged to provide linkage points for mycolic acids. An attractive arrangement can be envisaged with the galactan extending to a level similar to that of the peptidoglycan helix to produce an essentially level “mosaic platform” as a stable anchorage for mycolic acids. While the helical galactan can provide a relatively rigid base unit, the arabinan may be more flexible so that the bound mycolic acids can jostle for position and occupy optimal locations. Indeed, arabinan flexibility may be an important factor in allowing hydrophobic interactions to govern the relative location of mycolic acid chains and associated free lipids. Calculations  indicate that the arabinofuranose polymer is reluctant to adopt a rigid compact helical conformation, thereby allowing a degree of flexibility.
10. Cell envelope organisation
The original model , with an inner and outer membrane, was based mainly on chemical principles, supported by freeze-etching results  that showed two clear distinct parallel cleavage planes in the mycobacterial cell envelope. The dual membrane proposal was confirmed by a confocal microscopy study that showed differential location of two fluorescent dyes of different lipophilicity . The outer membrane was visualised directly by cryo-electron microscopy and the essential dimensions of the mycobacterial cell envelope were revealed [7-9]. An updated model for the cell envelope organisation for tubercle bacilli is proposed in Figure 10. Justification for the details of the proposal will build outwards from the plasma membrane.
The inner plasma membrane in mycobacteria has been traditionally regarded as conventional, even though a significant role was lacking for the unusual phosphatidylinositol mannosides (PIMs) (Figure 7). A resolution of this conundrum has been indicated in a study , which showed strong evidence for locating Ac2PIM2 (Figure 7) as the sole polar component of the inner leaflet of the inner membrane. It was suggested that PIM6 would be present in the outer leaflet of the inner membrane, projecting into the periplasm. It is not clear why there are two versions of PIM2 and PIM6, with either three or four fatty acid chains (Figure 7), but as a working hypothesis both PIM2 lipids are placed in the inner leaflet and both PIM6 lipids in the outer leaflet of the plasma membrane (Figure 10). As demonstrated by two-dimensional thin-layer chromatography , the proportions of the principal four PIM types are remarkably consistent, as is the proportion of PI. It is possible that equal proportions of PIMs with three and four fatty acid constituents are optimal for close packing in membranes; detailed physical studies on these lipids would be instructive. The proportions of PIM2 exceed those of PIM6 so if PIM2 lipids are considered to predominate in the inner leaflet , then PI, PE and DPG (Figure 7) may complete the outer leaflet along with PIM6. There is a distinct possibility that mycobacterial inner plasma membranes, rich in PIMs with three and four fatty acid chain anchors, have special physical properties that enhance its stability and perhaps governs permeability. Indeed, it has been suggested that this inner membrane may be “a bilayer environment of unusually low fluidity”  contributing to drug resistance. It was also noted  that the behaviour of PIM2 liposomes had been found  to have behaviour suggestive of exceptional stability. It is now apparent that the inner mycobacterial plasma membrane is a highly specialised organelle, worthy of being distinguished with special nomenclature. Given the developing popularity of “MOM” for the mycobacterial outer membrane, a related simple suggestion might be “MIM” for the “mycobacterial inner membrane”. It was found that disruption of PIM2 production causes growth arrest [67,68] but the higher PIMs were dispensable , thereby indicating an important structural role for PIM2. It has also been indicated that the acylation state of PIMs is also significant .
The outer leaflet of the MIM inner plasma membrane is also a suggested location for the PIM-related LM and LAM (Figure 10), but unequivocal evidence is elusive with alternative MOM location being a possibility. In a well-balanced objective analysis , it was concluded that LAM had at least an initial anchorage in MIM. However, in some cases [72,73], the undoubted presence of LAM at the cell surface required invoking specific lipoglycan transport mechanisms that need to be fully defined. At least a transient MIM location for LAM is supported by the presence of related lipoglycans in other actinomycetes, which do not have mycolic acids and an outer membrane, as summarised recently . The basic fact that the lipid anchors of LM and LAM are identical to those in PIMs (Figures 7,8) suggests very strongly that all these components have a common anchorage in MIM. This should not rule out possible interactions with the hydrophobic MOM surface, but such lipophilic binding is predictably less specific and it is very difficult to envisage LM and LAM as important integral components of the MOM outer leaflet. The PIM-based lipid anchors appear to be all very similar for related LM and LAM lipoglycans across the genus
The extensive supposed “periplasmic space” (Figure 10) will, in fact, be an area of intense activity as all cellular components of the MOM whose synthesis is initiated in the cytoplasm, and continued through MIM, may be assembled and organised within [51-54]. The fact that many of these cell envelope components are relatively large may explain why such a relatively extensive compartment is needed. Cryo-electron microscopy studies [7-9,76] gave indications of some rather indistinct structural elements within the periplasm, labelled as layers L1 and L2 [7,76]. The internal L1 layer is most probably associated with “granular” material of protein origin, with the outer L2 layer corresponding to some of the peptidoglycan-arabinogalactan matrix . It has been proposed that the maintenance of the relatively low-density periplasmic space could be facilitated by the presence of large polymeric material . The helical mannan polysaccharide moiety in LM (Figure 10) may have such a role, but it could also act as a scaffold or template to compartmentalise various biochemical activities. In
The accommodation and conformation of the mycoloyl arabinogalactan peptidoglycan macromolecular structure is a major challenge in the relatively limited space available (Figure 10). An informed choice has been made to use the “scaffold” approach of [61,62], with a helical peptidoglycan network interspersed with helical galactan units, as detailed in Figure 10. The relatively heavy peptidoglycan peptide cross-linking  may be a factor in favouring the scaffold arrangement in mycobacteria. This proposal echoes a previously advanced arrangement  that did not attempt to make precise spatial correlations and neglected to include the extensive periplasm. It would be interesting to explore the possibility that the
A wide range of free lipid types are considered to form the outer leaflet of the outer mycomembrane of members of the
11. Evolutionary and pathogenicity aspects of cell envelope composition
It is of particular interest to attempt to obtain an understanding of the influence and importance of cell envelope composition in mycobacterial pathogenicity and evolution. A consensus is developing that an attractive evolutionary pathway can be envisaged from environmental
The most fundamental underlying difference between members of the
There are also very significant changes in cell envelope MOM free lipid composition between all the taxa, shown in Figure 11.
Aspects of the cell envelope lipid composition of
Previous studies have shown an important link between hydrophobicity and aerosol performance in
A jump from environmental
It is conceivable that, during the Pleistocene, thinly spread members of
The cell envelope of
Given the hypothesis that tubercle bacilli evolved from an environmental organism, such as
The Leverhulme Trust Project Grant F/00 094/BL (OY-CL, DEM, GSB). GSB was supported by a Personal Research Chair from Mr. James Bardrick and the UK Medical Research Council. The UK Medical Research Council and the Medical Research Foundation provided support to AB.
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