Mycolic Acid and Arabinogalactan Biosynthesis in Mycobacteria

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Chapter: Pharmaceutical Microbiology : Mechanisms of action of antibiotics and synthetic anti-infective agents

The cell walls of mycobacteria contain an arabinogalactan polysaccharide in addition to the peptidoglycan, plus a variety of high molecular weight lipids, including the mycolic acids, glycolipids, phospholipids and waxes.


MYCOLIC ACID AND ARABINOGALACTAN BIOSYNTHESIS IN MYCOBACTERIA

 

The cell walls of mycobacteria contain an arabinogalactan polysaccharide in addition to the peptidoglycan, plus a variety of high molecular weight lipids, including the mycolic acids, glycolipids, phospholipids and waxes. The lipid-rich nature of the mycobacterial wall is responsible for the characteristic acid-fastness on staining and serves as a penetration barrier to many antibiotics. Isoniazid and ethambutol have long been known as specific antimycobacterial agents, exerting no activity towards other bacteria, but their mechanisms of action have only recently been established.

 

Isoniazid

 

Isoniazid interferes with mycolic acid synthesis by inhibiting an enoyl reductase (InhA) which forms part of the fatty acid synthase system in mycobacteria. Mycolic acids are produced by a diversion of the normal fatty acid synthetic pathway in which short-chain (16-carbon) and longchain (24-carbon) fatty acids are produced by addition of 7 or 11 malonate extension units from malonyl coenzyme A to acetyl coenzyme A. InhA inserts a double bond into the extending fatty acid chain at the 24-carbon stage. The long-chain fatty acids are further extended and condensed to produce the 60-90-carbon β-hydroxymycolic acids which are important components of the mycobacterial cell wall. Isoniazid is converted inside the mycobacteria to a free radical species by a catalase peroxidase enzyme, KatG. The active free radicals then attack and inhibit the enoyl reductase, InhA, by covalent attachment to the active site.

 

Ethambutol

 

Ethambutol blocks assembly of the arabinogalactan polysaccharide by inhibition of an arabinotransferase enzyme. Cells treated with ethambutol accumulate the isoprenoid intermediate deca-prenylarabinose, which supplies arabinose units for assembly in the arabinogalactan polymer.

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