Reversal of antifungal resistance mediated by ABC efflux pumps from Candida albicans functionally expressed in yeast

Schuetzer-Muehlbauer, Manuela; Willinger, Birgit; Egner, Ralf; Ecker, Gerhard F.; Kuchler, Karl

doi:10.1016/s0924-8579(03)00213-9

Cited by 86 publications

(69 citation statements)

References 56 publications

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“…EUKARYOT. CELL B and i [46]). Moreover, CASP-induced flocculation occurred in clinical isolates of C. tropicalis and C. lusitaniae also (data not shown).…”

Section: Resultsmentioning

confidence: 97%

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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“…EUKARYOT. CELL B and i [46]). Moreover, CASP-induced flocculation occurred in clinical isolates of C. tropicalis and C. lusitaniae also (data not shown).…”

Section: Resultsmentioning

confidence: 97%

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

et al. 2011

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“…Theˆrst involves ATP-binding cassette transporters (ABC, coded by CDR genes), which are ATP-dependent active transporters. 10,11) In C. albicans, eOEux pumps in the ABC superfamily include Cdr1p and Cdr2p, coded by CDR1 and CDR2, respectively. 8,9,11) EOEux pumps belonging to this superfamily are ubiquitously present and structurally similar in organisms ranging from prokaryotic cells to mammals.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Tetrandrine, a Natural Inhibitor of <i>Candida albicans</i> Drug Efflux Pumps

Zhao

Gao

et al. 2009

YAKUGAKU ZASSHI

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Synergistic eŠects have previously been observed for a natural compound, tetrandrine (TET), with ‰uconazole (FLC) in vitro and in the treatment of Candida albicans-infected mice. To investigate the mechanisms of these synergistic eŠects, 16 strains of C. albicans from the same parent but with diŠerent FLC sensitivities were examined using ‰ow cytometry and ‰uorescent spectrophotometry. Rhodamine 123 (Rh123)-positive cells and intracellular Rh123 ‰uores-cence intensity were determined in accumulation/eOEux experiments involving no or a noncytotoxic dose of TET. Total RNA extracted from each strain was used to compare the expressions of drug eOEux pump genes in FLC-susceptible, -susceptible dose-dependent, and -resistant strains before and 24 h after TET administration. Accumulation experiments determined that mean percentages of Rh123-positive cells were 26.65％ (TET-free) and 70.99％ (TET 30 mg/ml), and mean respective intracellular Rh123 ‰uorescence intensities were 11.34 and 18.00. EOEux experiments showed that percentages of Rh123-positive cells were 1.79％ (TET free) and 42.57％ (TET 30 mg/ml), respectively, and respective mean intracellular Rh123 ‰uorescence intensities were 0.74 and 2.19. DiŠerences in MDR1, FLU1, CDR1, and CDR2 expression levels in the absence of TET were statistically signiˆcant ( p＜0.05) between FLC-susceptible, -susceptible dosedependent, and -resistant strains. Compared with TET-free conditions, 24 h TET-treated strains showed statistically diŠerent ( p＜0.05) expression of MDR1 (FLC-resistant strain), FLU1 (FLC-susceptible dose-dependent and -resistant strains), and CDR1 and CDR2 (FLC-susceptible, -susceptible dose-dependent, and -resistant strains). Thus TET can inhibit the C. albicans drug eOEux system and reduce drug eOEux. Its mechanism of action is related to the inhibition of expression of the drug eOEux pump genes MDR1, FLU1, CDR1, and CDR2.

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“…In fact, calcineurin inhibition renders the normally fungistatic azoles fungicidal to several Candida species (437). It is important to note that FK506 and cyclosporine have other targets in the cell besides calcineurin, including multidrug transporters (483,513). However, synergy between cyclosporine and fluconazole was confirmed in vitro and in vivo for strains lacking drug transporters implicated in azole resistance (364).…”

Section: Cellular Stress Responsesmentioning

confidence: 99%

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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Reversal of antifungal resistance mediated by ABC efflux pumps from Candida albicans functionally expressed in yeast

Cited by 86 publications

References 56 publications

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

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

Mechanism of Action of Tetrandrine, a Natural Inhibitor of <i>Candida albicans</i> Drug Efflux Pumps

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

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