The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus

The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus

The continuous use of triazoles can result in the development of drug resistance. Azole-resistant clinical isolates, spontaneous and induced mutants of Aspergillus fumigatus have been documented. The azoles block the ergosterol biosynthesis pathway by inhibiting the enzyme 14- -demethylase, product...

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Bibliographic Details
Published in:Medical mycology (Oxford) Vol. 43; no. S1; pp. 313 - 319
Main Authors: Da Silva Ferreira, M. E., Colombo, A. L., Paulsen, I., Ren, Q., Wortman, J., Huang, J., Goldman, M. H. S., Goldman, G. H.
Format: Journal Article
Language:English
Published: UK Informa UK Ltd 01-05-2005
Subjects:
Antifungal Agents - pharmacology
Aspergillus fumigatus
Aspergillus fumigatus - drug effects
Aspergillus fumigatus - genetics
Aspergillus fumigatus - metabolism
ATP-Binding Cassette Transporters - genetics
ATP-Binding Cassette Transporters - metabolism
Azoles - pharmacology
Drug Resistance, Fungal
Ergosterol - biosynthesis
Fungal Proteins - genetics
Fungal Proteins - metabolism
Humans
Microbial Sensitivity Tests
Neurospora crassa
Saccharomyces cerevisiae
transporters
azoles
ergosterol
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Summary:The continuous use of triazoles can result in the development of drug resistance. Azole-resistant clinical isolates, spontaneous and induced mutants of Aspergillus fumigatus have been documented. The azoles block the ergosterol biosynthesis pathway by inhibiting the enzyme 14- -demethylase, product of the CYP51. Fungal azole resistance involves both amino acid changes in the target site that alter drug-target interactions and those that decrease net azole accumulation. The reduced intracellular accumulation has also been correlated with overexpression of multidrug resistance (MDR) efflux transporter genes of the ATP-binding cassette (ABC) and the major facilitator superfamily (MFS) classes. About 20 genes are involved in the A. fumigatus ergosterol biosynthesis pathway. There are several duplicated genes in this pathway. Interestingly, erg3 and erg11 showed two copies in A. fumigatus. In general, Aspergillus spp. have proportionally more MFS transporter encoding genes than Saccharomyces cerevisiae, S. pombe, and Neurospora crassa. The drug:H+ (12 and 14 spanners) sub-families are also proportionally greater than in the other species. Although the numbers of ABC transporter encoding genes are comparable, again the Aspergillus spp. have more ABC transporters related to multidrug permease than the other fungal species.
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ISSN:1369-3786
1460-2709
DOI:10.1080/13693780400029114