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Biomarkers of caspofungin resistance in Candida albicans isolates: A proteomic approach.

ABSTRACT: Candida albicans is a clinically important polymorphic fungal pathogen that causes life-threatening invasive infections in immunocompromised patients. Antifungal therapy failure is a substantial clinical problem, due to the emergence of an increasing number of drug-resistant isolates. Caspofungin is a common antifungal drug, often used as first-line therapy that inhibits cell wall β-(1,3)-glucan synthesis. In this work, the cell surface of different echinocandin-resistant C. albicans clinical isolates was compared with sensitive isolates and their responses to echinocandin treatment analyzed. Proteomic analysis detected changes in the repertoire of proteins involved in cell wall organization and maintenance, in drug-resistant strains compared to susceptible isolates and after incubation with caspofungin. Moreover, an interaction network was created from the differential expression results. Our findings suggest drug resistance may involve not only a different cell wall architecture, but also a different response to drugs.

SUBMITTER: De Cesare GB

PROVIDER: S-EPMC9225221 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Biomarkers of caspofungin resistance in Candida albicans isolates: A proteomic approach.

De Cesare Giuseppe Buda GB Hafez Ahmed A Stead David D Llorens Carlos C Munro Carol A CA

Virulence 20221201 1

Candida albicans is a clinically important polymorphic fungal pathogen that causes life-threatening invasive infections in immunocompromised patients. Antifungal therapy failure is a substantial clinical problem, due to the emergence of an increasing number of drug-resistant isolates. Caspofungin is a common antifungal drug, often used as first-line therapy that inhibits cell wall β-(1,3)-glucan synthesis. In this work, the cell surface of different echinocandin-resistant C. albicans</ ...[more]

PMID: 35730400

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Project description:Resistance to azole antifungals continues to be a significant problem in the common fungal pathogen Candida albicans. Many of the molecular mechanisms of resistance have been defined with matched sets of susceptible and resistant clinical isolates from the same strain. Mechanisms that have been identified include alterations in the gene encoding the target enzyme ERG11 or overexpression of efflux pump genes including CDR1, CDR2, and MDR1. In the present study, a collection of unmatched clinical isolates of C. albicans was analyzed for the known molecular mechanisms of resistance by standard methods. The collection was assembled so that approximately half of the isolates were resistant to azole drugs. Extensive cross-resistance was observed for fluconazole, clotrimazole, itraconazole, and ketoconazole. Northern blotting analyses indicated that overexpression of CDR1 and CDR2 correlates with resistance, suggesting that the two genes may be coregulated. MDR1 overexpression was observed infrequently in some resistant isolates. Overexpression of FLU1, an efflux pump gene related to MDR1, did not correlate with resistance, nor did overexpression of ERG11. Limited analysis of the ERG11 gene sequence identified several point mutations in resistant isolates; these mutations have been described previously. Two of the most common point mutations in ERG11 associated with resistance, D116E and E266D, were tested by restriction fragment length polymorphism analysis of the isolates from this collection. The results indicated that the two mutations occur frequently in different isolates of C. albicans and are not reliably associated with resistance. These analyses emphasize the diversity of mechanisms that result in a phenotype of azole resistance. They suggest that the resistance mechanisms identified in matched sets of susceptible and resistant isolates are not sufficient to explain resistance in a collection of unmatched clinical isolates and that additional mechanisms have yet to be discovered.

Project description: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. Single-nucleotide-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.

Dataset Information

Biomarkers of caspofungin resistance in Candida albicans isolates: A proteomic approach.

Publications

Biomarkers of caspofungin resistance in <i>Candida albicans</i> isolates: A proteomic approach.

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