The R467K Amino Acid Substitution in
            <i>Candida albicans</i>
            Sterol 14α-Demethylase Causes Drug Resistance through Reduced Affinity

Lamb, David C.; Kelly, Diane; White, Theodore C.; Kelly, Steven L.

doi:10.1128/aac.44.1.63-67.2000

Cited by 117 publications

(71 citation statements)

References 21 publications

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“…In addition, thus far, at least 12 different point mutations in Erg11, clustering into three distinct "hot-spot" regions, have been associated with azole resistance in clinical isolates (365). Biochemical analyses confirmed that mutations in Erg11 observed in the clinic decrease the affinity of azole binding in vitro (303). To determine the functional consequence of Erg11 mutations in vivo in the absence of other resistance mechanisms, ERG11 alleles were cloned from a series of C. albicans clinical isolates and expressed in the model yeast S. cerevisiae (503).…”

Section: Alteration Of the Drug Targetmentioning

confidence: 68%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Alteration Of the Drug Targetmentioning

confidence: 68%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

View full text Add to dashboard Cite

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“…Among the several nucleotide polymorphisms observed in separate ERG11 alleles, at least 12 mutations have been associated with azole resistance when separate alleles were expressed in Saccharomyces cerevisiae (1, 29). The majority of these mutations alters the binding of azoles to Erg11p (21,22,24,25,43). The upregulation of ERG11 has also been observed in several azole-resistant clinical isolates (2,17,24,34,53).…”

mentioning

confidence: 99%

Genotypic Evolution of Azole Resistance Mechanisms in Sequential Candida albicans Isolates

et al. 2007

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TAC1 (for transcriptional activator of CDR genes) is critical for the upregulation of the ABC transporters CDR1 and CDR2, which mediate azole resistance in Candida albicans. While a wild-type TAC1 allele drives high expression of CDR1/2 in response to inducers, we showed previously that TAC1 can be hyperactive by a gain-of-function (GOF) point mutation responsible for constitutive high expression of CDR1/2. High azole resistance levels are achieved when C. albicans carries hyperactive alleles only as a consequence of loss of heterozygosity (LOH) at the TAC1 locus on chromosome 5 (Chr 5), which is linked to the mating-type-like (MTL) locus. Both are located on the Chr 5 left arm along with ERG11 (target of azoles). In this work, five groups of related isolates containing azole-susceptible and -resistant strains were analyzed for the TAC1 and ERG11 alleles and for Chr 5 alterations. While recovered ERG11 alleles contained known mutations, 17 new TAC1 alleles were isolated, including 7 hyperactive alleles with five separate new GOF mutations. Singlenucleotide-polymorphism analysis of Chr 5 revealed that azole-resistant strains acquired TAC1 hyperactive alleles and, in most cases, ERG11 mutant alleles by LOH events not systematically including the MTL locus. TAC1 LOH resulted from mitotic recombination of the left arm of Chr 5, gene conversion within the TAC1 locus, or the loss and reduplication of the entire Chr 5. In one case, two independent TAC1 hyperactive alleles were acquired. Comparative genome hybridization and karyotype analysis revealed the presence of isochromosome 5L [i(5L)] in two azole-resistant strains. i(5L) leads to increased copy numbers of azole resistance genes present on the left arm of Chr 5, among them TAC1 and ERG11. Our work shows that azole resistance was due not only to the presence of specific mutations in azole resistance genes (at least ERG11 and TAC1) but also to their increase in copy number by LOH and to the addition of extra Chr 5 copies. With the combination of these different modifications, sophisticated genotypes were obtained. The development of azole resistance in C. albicans is therefore a powerful instrument for generating genetic diversity.Azoles belong to a class of antifungals that are widely used for the treatment of fungal diseases and especially those caused by Candida albicans. Since azoles are fungistatic drugs for C. albicans, cells repetitively exposed to these antifungals adapt to the drug pressure and eventually become azole resistant. In C. albicans, the occurrence of azole resistance has been observed in different patient groups, mostly in human immunodeficiency virus (HIV)-positive patients with oropharyngeal candidiasis (45). Azole resistance mechanisms have been investigated at the molecular level by several authors (1, 42, 55) and fall into different categories. First, alterations such as point mutations or upregulation of the gene encoding the target of azoles, an enzyme (Erg11p) involved in ergosterol biosynthesis, can occur. Among the several nucleotide ...

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“…In C. albicans, mutations that affect the affinity of the target enzyme Erg11p for azole antifungal drugs have been well documented as a drug-resistance mechanism [41][42][43][44][45][46]. In C. dubliniensis, Perea et al [31] have described mutations in the CdERG11 gene which were associated with fluconazole resistance.…”

Section: Mechanisms Of Azole Resistance In C Dubliniensismentioning

confidence: 99%

Azole susceptibility and resistance in Candida dubliniensis

Pinjon

Moran

Coleman

et al. 2005

Biochem. Soc. Trans

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Candida dubliniensis is a recently described species of pathogenic yeast that shares many phenotypic features with Candida albicans. It is primarily associated with oral colonization and infection in HIV-infected individuals. Isolates of C. dubliniensis are generally susceptible to commonly used azole antifungal agents; however, resistance has been observed in clinical isolates and can be induced by in vitro exposure. Molecular mechanisms of azole resistance in C. dubliniensis include increased drug efflux, modifications of the target enzyme and alterations in the ergosterol biosynthetic pathway.

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The R467K Amino Acid Substitution in Candida albicans Sterol 14α-Demethylase Causes Drug Resistance through Reduced Affinity

Cited by 117 publications

References 21 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Genotypic Evolution of Azole Resistance Mechanisms in Sequential Candida albicans Isolates

Azole susceptibility and resistance in Candida dubliniensis

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