Mycobacterial cell wall

The antimicrobial action of ethambutol, like that of isoniazid, is specific for mycobacteria, suggesting a target in the unique components of the mycobacterial cell wall. Cells treated with ethambutol accumulate an isoprenoid intermediate, decaprenyl-arabinose which is the source ofarabinose in the arabinogalactan polymer. This suggests that ethambutol blocks assembly of the arabinogalactan through inhibition of an arabinosyl transferase enzyme. 

Barry C.E. Mdluli K. (1996) Drug sensitivity and environmental adaptation of mycobacterial cell wall components. Trends Microbiol, 4, 275-281. 

Overall, the mechanisms involved in the role of the mycobacterial cell wall as a permeability barrier are poorly understood and it is not known why MAI and M. chelonae, in particular, are more resistant than other species of mycobacteria. 

The answer is a. (Hardman, p 1157. Katzung, p 804J Isoniazid inhibits mycobacterial cell-wall synthesis by inhibiting my colic acid synthesis by a mechanism that is not fully understood. 

Fractionation of mycobacteria resulted in the identification of two cellular immunostimulatory components, namely TDM and MDPs. Both are normally found in association with the mycobacterial cell wall. TDM is composed of a molecule of trehalose (a disaccharide consisting of two molecules of a-D-glucose linked via an a 1-1 glycosidic bond), linked to two molecules of my-colic acid (a long-chain aliphatic hydrocarbon-based acid) found almost exclusively in association with mycobacteria. TDM, although retaining its adjuvanticity, is relatively non-toxic. 

Cyclopropyl fatty acids with C12, Cjg and C21 have been formed in many gram-negative and gram-positive bacteria [198]. The mycolic acid 142 (Cso) is a major component of the mycobacterial cell wall of the human strain of M. tuber-culosiSyEq. (57) [199]. 

Isoniazid (INH) is a synthetic derivative of isonico-tinic acid. It has bactericidal activity against both intra- and extra-cellular mycobacteria. It also displays anti-bacterial activity in caseous lesions, but only in proliferating cells. Losing genes which code for catalase and peroxidase is the major mechanism through which resistance occurs. Single mutations can rapidly result in such resistance if isoniazid is used alone. Its mechanism of action is presumably based on inhibition of the synthesis of mycolic acids, unique and essential components of the mycobacterial cell wall. 

Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis. Nearly all strains of M tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensitive to ethambutol. Drug resistance relates to point mutations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis. 

Isoniazid possibly exerts its action by inhibiting the synthesis of mycolic acid which is an essential component of mycobacterial cell wall. It is also postulated that the ability of isoniazid to suppress the formation of DNA and RNA and also inhibition of various oxidative mechanisms may be responsible for its action. 

Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1-5 mcg/mL. Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene. 

Isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls Bactericidal activity against susceptible strains of M tuberculosis First-line agent for tuberculosis treatment of latent infection less active against other mycobacteria Oral, IV hepatic clearance (half-life 1 h) reduces levels of phenytoin Toxicity Flepatotoxic, peripheral neuropathy (give pyridoxine to prevent)... 

Ethambutol Inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan an essential component of the mycobacterial cell wall Bacteriostatic activity against susceptible mycobacteria Given as four-drug initial combination therapy for tuberculosis until drug sensitivities are known also used for atypical mycobacterial infections Oral t mixed clearance (half-life 4 h) dose must be reduced in renal failure Toxicity Retrobulbar neuritis... 

Bacterial DNA, long a component of the earlier whole cell vaccines, has been shown to have an immunostimulatory effect on immune cells and is a potent inducer of cytokines such as IL-1, IL-6, and IL-12. Monophosphoryl A, a component of mycobacterial cell walls, reacts with receptors on antigen producing cells and generates a Thl response due to the production of IL-2 and IFN-y. 

The mycobacterial cell wall, discussed in Chapter 8, contains mycolic acids bound covalently at the nonreducing ends of arabinogalac-tans that are attached to the inner peptidoglycan layer,e as well as phosphatidylinositol-anchored lipoarabinomannans. Other unusual lipids that are also present and account for some of the difficulty of treatment with antibiotics include esters of mycocerosic acid with long-chain diols known as phenolphthiocerols and phthiocerols.f/fg... 

Other monosaccharide components (of bacterial polysaccharides) that are structurally related to D-ribose include D-riburonic acid,232 identified in the exocellular polysaccharide produced by a strain of Rhizobium meliloti, and D-arabinose, frequently present as the furanose, in polysaccharides of mycobacterial cell-wall.233,234 L-Xylose235,236 should probably be included in the group, as it may be derived from D-arabinose through epimerization at C-4. Biosynthesis of these monosaccharides was not investigated. 

Several studies concerning D-mannosyl transfer from GDP-Man and Man-p-Pre onto unidentified acceptors in Mycobacteria have been published.67,393 The enzymic system may use methyl a-D-mannopyranoside as the exogenous acceptor for D-mannosyl transfer.394 In this case, formation of a-(l- 2) linkages was observed they are present in 3-O-methyl-D-mannose-containing polysaccharides and a D-arabino-D-mannan characteristic of mycobacterial cell-wall. 

When crude endotoxin from the heptose-less mutant of Salmonella typhimurium is combined with trehalose dimycolate from mycobacteria in oil droplets and injected directly into established tumors (line 10 hepatocellular carcinoma) in syngeneic guinea pigs, rapid regression of the tumors occurs and over 90% of the animals are cured. The three required components for activity in this tumor model are (a) the endotoxin (b) the mycobacterial adjuvant, trehalose dimycolate and (c) a compound satisfying the minimal structural requirement (muramyl dipeptide) for adjuvant activity by bacterial cell wall materials. The mycobacterial cell wall skeleton is able to replace the latter two components. 

Additionally, the synthesis of mycobacterial cell-wall fragments were carried out by many groups. Oligoarabinofuranosides [183,184, 204] and other fragments... 

The porins present in mycobacterial cell walls probably permit the entry of... 

The component(s) of the mycobacterial cell wall responsible for conferring intrinsic resistance to antibiotics are not yet known with any certainty. However, it has been shown [91-93] that inhibitors of arabinogalactan synthesis increase mycobacterial sensitivity to antibiotics. When M. avium is treated with inhibitors of mycolic acid biosynthesis there are significant alterations in outer cell wall layers and the cells show an increased antibiotic susceptibility [93], Thus, arabinogalactan and mycolic acids are components of the wall associated with intrinsic resistance of mycobacteria to chemotherapeutic drugs and alteration of these structural building blocks leads to increased intracellular penetration of antibiotics [88,94,95],... 

Many years ago, it was proposed [105] that resistance of mycobacteria to QACs was related to the lipid content of the cell wall thus, M. phlei (with low total lipid) was more sensitive than M. tuberculosis, which possessed a higher total cell lipid content. It was also pointed out [105] that the resistance of various species of mycobacteria was related to the content of waxy material in the wall. As noted above, the mycobacterial cell wall is highly hydrophobic with a mycoylarabinogalactanpeptidoglycan skeleton. Hydrophilic type biocides are generally unable to penetrate the cell wall in sufficiently high concentration to produce a lethal effect. However, low concentrations... 

Multidrug-resistant M. tuberculosis (MDRTB) strains have become a problem. As pointed out previously, the mycobacterial cell wall presents a major barrier to the entry of chemotherapeutic drugs. Possible solutions are (i) to design drugs of increasing hydrophobicity that will pass through the cell wall, as with isoniazid derivatives [89, 90], (ii) to use a second antibiotic in combination with a known inhibitor of arabinogalactan or mycolic acid biosynthesis [238]. 

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