Ergosterol biosynthesis inhibition: a target for antifungal agents.
The isoprenoid sterols play a crucial role in the viability of all fungi; those unable to synthesise ergosterol because of inhibition, growth conditions or mutation must take it up from the environment. A range of compound types have been discovered which interfere with the biosynthetic pathway from acetate to ergosterol and these compounds have antifungal actions. Inhibition of several of the steps has yielded agents which have been used with great success as medical and agrochemical agents. The most important biosynthetic steps that have been exploited are inhibition of squalene epoxidase, (the allylamines and tolnaftate) C14 demethylation (the azoles), delta 7,8 isomerase and delta 14 reductase which are inhibited by the morpholines. Recent research has shown that inhibition of C24 methyltransferase and C4 demethylation also yield antifungal agents. Combination studies demonstrate that synergy between agents of different types can be measured. Fungicidal effects were observed when a combination of two fungistatic agents was used.
Barrett-Bee
K
K
Infection Research Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Dixon
G
G
D000935:Antifungal Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D004875:Ergosterol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D008745:Methylation; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
D000935:Antifungal Agents; D004798:Enzymes; D005493:Folic Acid Antagonists; D013449:Sulfonamides; D004875:Ergosterol