The <i>Candida albicans</i> Cdr2p ATP‐binding cassette (ABC) transporter confers resistance to caspofungin

Schuetzer-Muehlbauer, Manuela; Willinger, Birgit; Krapf, Gerd; Enzinger, Sabine; Presterl, Elisabeth; Kuchler, Karl

doi:10.1046/j.1365-2958.2003.03430.x

Cited by 109 publications

(63 citation statements)

References 58 publications

(77 reference statements)

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“…Experimental studies suggested that the Cdr drug pumps may play a minor role in echinocandin resistance. When Cdr2 was expressed in S. cerevisiae, an increase in resistance to caspofungin was observed (514). Likewise, Cdr2 increased caspofungin resistance when constitutively overexpressed in a drug-sensitive C. albicans strain (514).…”

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 99%

“…When Cdr2 was expressed in S. cerevisiae, an increase in resistance to caspofungin was observed (514). Likewise, Cdr2 increased caspofungin resistance when constitutively overexpressed in a drug-sensitive C. albicans strain (514). In contrast, it was observed that a C. albicans clinical isolate overexpressing both Cdr1 and Cdr2 exhibited reduced susceptibility to caspofungin and a slightly increased susceptibility to micafungin in agar plate assays (419).…”

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 99%

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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

492

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: Upregulation Of Multidrug Transportersmentioning

confidence: 99%

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

492

547

View full text Add to dashboard Cite

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“…Resistance to CASP is frequently associated with mutations in the FKS1 gene (1,17). An efflux-based mechanism that operates through the Cdr2 ABC transporter may also contribute to CASP tolerance in laboratory strains as well as in clinical isolates (47). C. albicans cells rapidly respond to CASP treatment, since cell wall stress triggers the C. albicans cell wall integrity protein kinase C signaling pathway (PKC).…”

mentioning

confidence: 99%

Efg1 Controls Caspofungin-Induced Cell Aggregation of Candida albicans through the Adhesin Als1

et al. 2011

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Echinocandin drugs such as caspofungin (CASP), micafungin, and anidulafungin inhibit fungal cell wall biogenesis by blocking Fks1-mediated ␤-glucan deposition into the cell surface. Candins have become suitable drugs to treat life-threatening diseases caused by several fungal species, including Candida albicans, that are pathogenic for humans. Here, we present the discovery of a novel CASP-induced flocculation phenotype of C. albicans, which formed large cell aggregates in the presence of CASP. High concentrations of sugars such as mannose or glucose inhibit CASP-induced flocculation and improve survival of C. albicans cells exposed to CASP. Notably, exposure of C. albicans cells to CASP triggers Efg1-dependent expression of the adhesin ALS1 and induces invasive growth on agar plates. Indeed, cells lacking either Efg1 or Als1 show strongly diminished CASP-induced flocculation, and the absence of Efg1 leads to marked CASP hypersensitivity. On the other hand, CASP-induced invasive growth is enhanced in cells lacking Efg1. Hence, CASP stress drives an Efg1-dependent response, indicating that this multifunctional transcriptional regulator, which is otherwise involved in filamentation, white-to-opaque switching, and virulence, also modulates cell wall remodeling upon CASP challenge. Taken together, our data suggest that CASP-induced cell wall damage activates Efg1 in parallel with the known cell integrity stress signaling pathway to coordinate cell wall remodeling.

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“…Yeast cells were grown overnight at 28 uC to mid-exponential phase and diluted to OD 600 =0?3 (9610 6 cells ml 21 ) in a volume of 200 ml YEPD. The cultures were allowed to grow for one generation before removing a 10 ml (1610 8 -2610 8 cells) aliquot which was processed as described by Reinoso-Martin et al (2003) and Schuetzer-Muehlbauer et al (2003). Four further 10 ml aliquots were dispensed into individual pre-warmed universals and incubated at 37 uC.…”

mentioning

confidence: 99%