Antifungal resistance does not necessarily affect<i>Candida glabrata</i>fitness

Borghi, Elisa; Andreoni, Stefano; Cirasola, Daniela; Ricucci, Valentina; Sciota, Rita; Morace, Giulia

doi:10.1179/1973947813y.0000000100

Cited by 20 publications

(18 citation statements)

References 28 publications

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“…FKS1 mutations cause cell wall stress and therefore altered fungal cell wall presentation to the immune cells at the expense of C. albicans survival. Interestingly, caspofungin resistance in C. glabrata is not associated with fitness costs, as measured in the minihost model Galleria mellonella; however, this effect has not been yet addressed in animal models (65). As a comparison, one of the few other studies in which engineered strains were used was on the effect of CgPDR1 GOF mutations involved in azole resistance on virulence.…”

Section: Discussionmentioning

confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

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Section: Discussionmentioning

confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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“…Similarly, Lackner et al found reduced kidney burden comparing sequential C. albicans clinical isolates with and without two heterogenous mutations simultaneously at position R647 and P649 (34). In contrast, Borghi et al found no significant difference in virulence or fitness when comparing sequential patient C. glabrata isolates with and without the S663P mutation in the Galleria mellonella larvae model (35). Either, this contradictory finding relates to the different virulence models used, i.e.…”

Section: Implication On Fitnessmentioning

confidence: 97%

Echinocandin resistance

Arendrup

Perlin²

2014

Current Opinion in Infectious Diseases

252

136

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Purpose of review Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as 1st line therapy for patients with invasive candidiasis. Here we review recent advances in our understanding of the epidemiology, underlying mechanisms, methods for detection and clinical implications. Recent findings Echinocandin resistance has emerged over the recent years. It has been found in most clinically relevant Candida species, but is most common in C. glabrata with rates exceeding 10% at selected institutions. It is most commonly detected after 3–4 weeks of treatment and is associated with a dismal outcome. An extensive list of mutations in hot-spot regions of the genes encoding the target has been characterised and associated with species and drug specific loss of susceptibility. The updated antifungal susceptibility testing reference methods identify echinocandin resistant isolates reliably; while the performance of commercial tests is somewhat more variable. Alternative technologies are being developed including molecular detection and MALDI-TOF. Summary Echinocandin resistance is an increasingly encountered and mandates susceptibility testing particularly in patients with prior exposure. The further development of rapid and user-friendly commercially available susceptibility platforms is warranted. Antifungal stewardship is important in order to minimise unnecessary selection pressure.

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“…This observation might be related to a high fitness cost for the yeast conferred by the acquisition of resistance. Currently, however, a fitness cost has been demonstrated only in vitro or in animal models [6,7]; it has not yet been documented in patients and is thus subject to various results [8].…”

Section: Introductionmentioning

confidence: 99%

Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia

Imbert

Castain

Pons

et al. 2016

Clinical Microbiology and Infection

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To give an indication of a fitness cost conferred by FKS mutation-associated echinocandin resistance in Candida glabrata during human infection. Six C. glabrata clinical strains sequentially isolated from blood and a hepatic abscess in a solid organ transplant recipient were analysed. The patient had received long-term azole and echinocandin therapy for invasive aspergillosis and persistent candidaemia. Minimal inhibitory concentrations were determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Molecular mechanisms of antifungal resistance were determined by sequencing hot spots of the FKS. Strain relatedness was determined using a microsatellite-based typing method. Typing analysis revealed an identical microsatellite pattern for all isolates, supporting a close relation. The first C. glabrata isolate showed wild-type phenotype (i.e. susceptibility to echinocandins and low level of azole resistance). After voriconazole therapy, the C. glabrata quickly acquired pan-azole resistance. Later, echinocandin treatment led to the emergence of a FKS2 S663P alteration and echinocandin resistance. After disruption of both azole and echinocandin therapy in favour of liposomal amphotericin B, C. glabrata isolates regained full susceptibility to echinocandin and lost the FKS2 S663P alteration while nonetheless maintaining their pan-azole resistance. Our clinical report supports the potential existence of a fitness cost conferred by FKS mutation in C. glabrata, as disruption of treatment led to a rapid disappearance of the resistant clone. This suggests that a more restricted use and/or a discontinuous administration of echinocandins may limit the spread of clinical resistance to this class.

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Antifungal resistance does not necessarily affectCandida glabratafitness

Cited by 20 publications

References 28 publications

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Echinocandin resistance

Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia

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