How do fungi become resistant to fluconazole?

Question by Tim S: How do fungi become resistant to fluconazole?
By fungi, I mean pathogenic fungi such as Candida albicans

Best answer:

Answer by Marilyn
The link below will take you to a discussion web site where you will also find Definition of Fluconazole Resistance, Prevention of Fluconazole-Resistant Candidiasis and Recommended Therapy for Fluconazole-Resistant Candidiasis.

Mechanisms for Fluconazole Resistance

Fluconazole exerts its action on the fungal membrane by inhibiting the synthesis of ergosterol, the predominant sterol in the fungal cell membrane[6]. Specifically, fluconazole blocks a step in the conversion of squalene to ergosterol by inhibiting the fungal cytochrome P-450 enzyme 14 alpha-demethylase (Figure 1)[6]. This inhibitory action prevents fungal cell replication and causes a build-up of lanosterol and other ergosterol precursors in the fungal cell membrane. The abnormalities in the fungal cell membrane eventually lead to cell death. The selective action of fluconazole for fungal cell membranes occurs because human cells use cholesterol, not ergosterol, for the synthesis of cell membranes. Resistance to fluconazole can develop as a result of an alteration in the target enzyme 14 alpha-demethylase (change in binding site or overexpression of the enzyme) or from enhanced drug efflux caused by plasma membrane transporters (Figure 2)[6,7,8,9,10]; many of the strains of fluconazole-resistant Candida species display multiple mechanisms of resistance[7].

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