Mechanisms of resistance to azole antifungals

• Autorzy: Marichal P. , Bossche H.V.
• Języki publikacji: EN

Abstrakty

EN

Until the late eighties, clinical resistance to azole antifungals was a rare pheno­menon. Only a few cases of resistance to ketoconazole were found in patients with chronic mucocutaneous candidiasis (CMC). The spread of AIDS and the widespread prophylactic and therapeutic use of the hydrophilic azole compound fluconazole resulted both in the selection and induction of resistant strains and in a shift in the nature of the infecting organisms. Most azole antifungals such as itraconazole, ketoconazole and fluconazole are active against a variety of fungal diseases. However, the concentration needed to inhibit growth is dependent on the nature of the infecting species. Mucor spp., e.g., are almost insensitive to present available azole compounds and can be regarded as intrinsically resistant to azole treatment. Physicochemical features, such as the hydrophobicity and pKa, of a given azole, define whether or not it will be active or cross-resistant against a given species. Fluconazole is almost inactive against Candida krusei and Aspergillus fumigatus, whereas the lipophilic itraconazole is active against these species. A third type of resistance is acquired or induced resistance. This is the most contro­versial type because, even within a given species, organisms may differ in their response to the same azole. For these strains, convincing evidence can only be obtained when there is a genotypically related strain, which does not show resistance. In a limited number of biochemical or molecular biological studies the mechanisms of resistance have been investigated at the molecular level. These studies show that resistance can occur when there is an insufficient intracellular content of the azole. This can be due to impermeability problems, inactivated uptake systems or, and more likely, the presence of active multidrug resistance gene products of the P-glycoprotein type. Alteration or overexpression of the target for azole antifungals, the cytochrome P450-dependent 14 a-demethylase, also induces resistance. The nature and amount of the accumulating sterols also are of great importance for azole-induced growth inhi­bition. This may explain why mutations in other enzymes of the ergosterol bio­synthesis pathway, e.g. the A5-6 desaturase, can contribute to azole resistance.

Słowa kluczowe

EN

chronic mucocutaneous candidiasis; Aspergillus fumigatus; intracellular content; fungal azole resistance; in vitro; fluconazole; Candida krusei; antifungal drug; candidiasis; Candida; ketoconazole; cytochrome P450; itraconazole

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 1995
• Tom: 42
• Numer: 4
• Opis fizyczny: p.509-516

Twórcy

autor

Marichal P.

• Janssen Research Foundation, Beerse, Belgium

autor

Bossche H.V.

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