Disease relevance of AZR1

• The study also demonstrates that azole resistance of oropharyngeal yeasts is a common problem in patients infected with human immunodeficiency virus type 1 and that this azole resistance has clinical relevance [1].

High impact information on AZR1

• The S484A enzyme retained half the wild type ATPase activity without affecting azole resistance, but the S307A enzyme was unstable to plasma membrane isolation [2].
• The changes also reduced the affinity of the enzyme for the azole antifungals ketoconazole and fluconazole and after expression induced by galactose caused 4-5-fold azole resistance in transformants of S. cerevisiae [3].
• Reintroduction of wild-type or F15 PDR1 fully reversed these effects; together these results demonstrate a role for this gene in both acquired and intrinsic azole resistance [4].
• In C. glabrata clinical isolates, the predominant mechanism behind azole resistance is upregulated expression of multidrug transporter genes CDR1 and PDH1 [4].
• These azole resistance-associated changes could affect C. glabrata tissue-specific virulence; in support of this, we detected differences in F15 oxidant, alcohol and weak acid sensitivities [4].

Biological context of AZR1

• These conclusions were based on the higher susceptibility to these compounds of an azr1Delta deletion mutant strain compared with the wild-type and on the increased resistance of both azr1Delta and wild-type strains upon increased expression of the AZR1 gene from a centromeric plasmid clone [5].
• AZR1 gene expression reduces the duration of acetic acid-induced latency, although the growth kinetics of adapted cells under acetic acid stress is apparently independent of AZR1 expression level [5].
• We show that the acetate sensitivity phenotype previously ascribed to yeast mutants lacking the Pdr12p and Azr1p plasma membrane transporters is an artefact arising from the use of trp1 mutant strains [6].
• To identify additional putative azole resistance genes in C. albicans, a genomic library from this organism was screened for complementation of fluconazole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5 [7].
• A correlation between upregulation of this gene and azole resistance was thus established [8].

Anatomical context of AZR1

• Expression of the AZR1 gene (ORF YGR224w), encoding a plasma membrane transporter of the major facilitator superfamily, is required for adaptation to acetic acid and resistance to azoles in Saccharomyces cerevisiae [5].
• On univariate analysis, more than five episodes of oral candidosis in the last year (P = 0.01), previous use of azole therapy (P = 0.001), C2-3 category of HIV infection (P = 0.01) and low number of circulating CD4+ T-cells (P = 0.03) were significantly associated with an increased risk for the development of azole resistance [9].
• These findings are in agreement with recent reports of increased azole resistance in Candida species in general and suggest the possibility that the oral cavity may act as a reservoir of resistant yeast isolates in systemic infections [10].

Associations of AZR1 with chemical compounds

• This MFS-MDR homologue is required for yeast adaptation to high stress imposed by low-chain organic acids, in particular by acetic acid, and for resistance to azoles, especially to ketoconazole and fluconazole; the encoding gene was thus named the AZR1 gene [5].
• Although most C. dubliniensis isolates are susceptible to fluconazole, the inducibility of azole resistance in vitro has been reported [11].
• These results provide an important link between changes in the ergosterol biosynthetic pathway and azole resistance in this opportunistic fungal species [12].
• Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals [13].
• Multiple amino acid substitutions in lanosterol 14alpha-demethylase contribute to azole resistance in Candida albicans [14].

Other interactions of AZR1

• We suggest that a Cka2p-dependent regulatory pathway is altered by clinically derived azole resistance mutations [15].
• Here, we show that overexpression of Saccharomyces P-450 14alphaDM in S. cerevisiae, under the control of the regulatable promoter GAL1, results in azole resistance [16].
• Replacement of one copy of ERG11 in an azole-susceptible strain of C. albicans with a single copy of the Darlington ERG11 resulted in expression of the integrated copy and a modest increase in azole resistance [17].
• PDR16-mediated azole resistance in Candida albicans [18].
• BM2 represents a novel class of broad-spectrum, surface-active, Pma1p-targeting fungicides which increases the potencies of azole drugs and circumvents azole resistance [19].

Analytical, diagnostic and therapeutic context of AZR1

• The results of this study suggest that azole resistance may become a clinical problem in palliative care [20].

References