Targeting the formation of the cell wall core of M. tuberculosis

Abstract

Mycobacteria have a unique cell wall, which is rich in drug targets. The cell wall core consists of a peptidoglycan layer, a mycolic acid layer, and an arabinogalactan polysaccharide connecting them. The detailed structure of the cell wall core is largely, although not completely, understood and will be presented. The biosynthetic pathways of all three components reveal significant drug targets that are the basis of present drugs and/or have potential for new drugs. These pathways will be reviewed and include enzymes involved in polyisoprene biosynthesis, soluble arabinogalactan precursor production, arabinogalactan polymerization, fatty acid synthesis, mycolate maturation, and soluble peptidoglycan precursor formation. Information relevant to targeting all these enzymes will be presented in tabular form. Selected enzymes will then be discussed in more detail. It is thus hoped this chapter will aid in the selection of targets for new drugs to combat tuberculosis.

Fig 1

The structure of the mycolyl arabinogalactan peptidoglycan core of M. tuberculosis. The mycolic acids are shown attached to two thirds of the arabinans in an all or nothing fashion but this is not known. It is known that they are attached to 4 neighboring non-reducing end arabinosyl groups rather than 1,2, or 3 [196]. Three arabinan chains per galactan are shown attached according to recent data [12] and the length of the arabinan are according to recent data in the author’s (M.M.) laboratory.

Fig 2

The biosynthesis of decaprenyl phosphate. The pathway can be seen as two parts, with the first part being the formation of the monomers dimethylallyl diphosphate and isopentyl diphosphate, and the second part being the polymerization utilizing those compounds.

Fig 3

The biosynthesis of the activated sugars required for AG biosynthesis: (A) The biosynthetic pathway for the formation of dTDP-Rha; (B) the biosynthetic pathway for the formation of UDP-Galf; (C) the biosynthetic pathway for the formation of decaprenylphosphoryl-D-arabinose.

Fig 4

The biosynthetic pathway of mycolyl arabinogalactan. The polymer is formed on decaprenyl phosphate as shown. The order of the later events is not yet known; the ligation to peptidoglycan is shown as the last step. However, the arabinan and mycolates or just the mycolates may be added after ligation to peptidoglycan. The addition of the succinyl residue is not shown and the addition of the GalNH₂ residue as shown in the figure is, in fact, speculative.

Fig 5

The biosynthetic pathway of mycolic acids. At the top of the figure the formation of activated C26-CoA is shown, which is one half of the condensation shown at the bottom of the figure. The remainder of the figure is concerned with the formation of the meromycolates. The pathway for the formation of the double bonds in the meromycolates remains unclear and two possibilities are shown. One of these requires isomerization of the normal cis double bond to trans, and the other the use of desaturase enzymes. These two possibilities are shown using dotted lines.

Fig 6

The formation of peptidoglycan. Shown is the standard PG formation pathway used by most bacteria with the only differences being the oxidation of the acetyl group on muramic acid to a glycolyl group. Not shown is the amidation and methylation of glycolipid II that has been recently demonstrated [28].