These surround the AG (arabinogalactan) and LAM (lipoarabinomannan) and are connected by the peptide cross-links (coloured circles: orange = L-alanine, yellow = D- isoglutamine, green = meso-diaminopimelate and blue = D-alanine). According to the ‘scaffold model’, the glycan back bone (purple) of the PG (peptidoglycan) forms a matrix of helices orientated perpendicular to the plasma membrane ( Dmitriev et al., 2000). Also anchored into the plasma membrane are LM (lipomannan) and LAM (lipoarabinomannan), which project out into the periplasm the mannose sugars and mannan domains are coloured light blue and the branched arabinan is green. The inner leaflet of the plasma membrane contains a high quantity of Ac 1/Ac 2PIM 2 (tri- and tetra-acylated phosphatidyl- myo-inositol-dimannoside), while the outer membrane has Ac 1/Ac 2PIM 6 (tri- and tetra-acylated phosphatidyl- myo-inositol-hexamannoside), along with the more usual phospholipids, DPG (diphosphatidylglycerol), PE (phosphatidylethanolamine) and PI (phosphatidylinositol) the methyl groups of the unique tuberculostearic acids of mycobacteria are depicted here ( Minnikin et al., 2015). The cell wall of Mycobacterium tuberculosis. 1 for examples in red), an understanding of the complex biosynthesis pathways and mechanisms of drug inhibition and resistance, is a valuable part of this research. As many of the current drugs, and those under development, target the cell wall (see Fig. ![]() This has resulted in a surge of research into mycobacteria, in the hopes of finding new effective drugs and targets. However, extensively drug resistant strains (XDR), which are additionally resistant to second-line drugs, are also emerging ( World Health Organisation, 2011). Second-line drugs, which include capreomycin, ethionamide and streptomycin, are the next level of treatment for those with resistant strains ( World Health Organisation, 2011). ![]() ![]() Since these drugs have been used for more than 60 years, multi-drug resistant strains (MDR) have developed, with mutations in the target enzymes or drug activation pathways. The first-line drug regimen is a combination of antibiotics, consisting of ethambutol, isoniazid, rifampicin and pyrazinamide ( World Health Organization, 2017). A crucial part of this pathogenicity is the extremely unusual cell wall of mycobacteria, and as such many of the current antibiotic regimes target essential enzymes involved in its synthesis. Mycobacterium tuberculosis ( Mtb), the causative agent of tuberculosis, has a mortality rate of over 1.5 million a year ( World Health Organisation, 2019). This review provides a synopsis of the structure and synthesis of the cell wall and the major current drugs and targets, along with any mechanisms of resistance. ![]() The flip side of this coin is that resistance to these drugs develops either in the target enzymes or the activation pathways of the drugs, paving the way for new resistant clinical strains. However, part of this success comes at a cost, with many of the current first- and second-line drugs targeting the enzymes involved in cell wall biosynthesis. This coat provides a protective hydrophobic barrier to antibiotics and the host’s defences, while enabling the bacterium to spread efficiently through sputum to infect and survive within the macrophages of new hosts. Part of this success relies on the unique cell wall, which consists of a thick waxy coat with tightly packed layers of complexed sugars, lipids and peptides. Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, is the global leading cause of mortality from an infectious agent.
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