A Target to Miss

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Science  22 Sep 2000:
Vol. 289, Issue 5487, pp. 2007
DOI: 10.1126/science.289.5487.2007c

The incidence of life-threatening fungal infections is on the increase, and so too is the incidence of fungal resistance to the standard azole drugs used to inhibit sterol 14a-demethylase, an enzyme required for the biosynthesis of ergosterol, which is an essential fungal cell membrane constituent. Polyenes are an alternative antibiotic, but these are unattractive due to their toxicity; therefore, the hunt is on to find other leads. Sterol biosynthesis has long been regarded as a potential target, both in medically important fungi and in plant crop diseases. Inhibition of an upstream enzyme in the sterol pathway, squalene synthase, in the laboratory yeast Saccharomyces cerevisiae leads to cell death, but its importance for pathogenic fungi in vivo has not been assessed.

Nakayama et al. made mutants of the pathogenic fungus Candida glabrata in which the gene for squalene synthase was turned off via a tetracycline-regulatable switch. Although growth in laboratory media was hampered, the C. glabrata mutant remained viable and pathogenic in mice. It turns out that the mutant fungus can scavenge cholesterol from the host serum to correct its defect, one reason why many of the ergosterol biosynthesis pathway inhibitors, some of which have been released for use in human infections, may be ineffective. — CA

Antimicrobial. Agents Chemother.44, 2411 (2000).

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