Regulation of multidrug resistance in pathogenic fungi

Morschhäuser, Joachim

doi:10.1016/j.fgb.2009.08.002

Cited by 256 publications

(204 citation statements)

References 185 publications

(268 reference statements)

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“…They contain two membrane-spanning domains and two nucleotide binding domains that utilize ATP to drive substrates across the membrane (90,390). CDR1 and CDR2 were both identified based on their ability to complement a PDR5 mutant in S. cerevisiae (466,505).…”

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

501

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%

“…MF drug pumps have no nucleotide binding domain but instead use the proton motive force of the membrane as an energy source (90,390). MDR1 is thus far the only MF gene cloned in medically important fungi, and it is involved specifically in resistance to fluconazole rather than other azoles (623).…”

Section: Upregulation Of Multidrug Transportersmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

501

547

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“…Gain-of-function mutations that result in constitutive activity of Mrr1 are located in different regions of the protein and are thought to affect amino acid residues that are important to keep the transcription factor in an inactive state in the absence of an inducer (21). Almost all gain-of-function mutations identified so far are located outside domains that can be predicted by sequence analysis, the DNA binding domain containing the Zn 2 Cys 6 motif and a conserved domain known as the middle homology region.…”

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confidence: 99%

Functional Dissection of a Candida albicans Zinc Cluster Transcription Factor, the Multidrug Resistance Regulator Mrr1

et al. 2011

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The overexpression of the MDR1 gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the widely used antimycotic agent fluconazole and other toxic compounds in the pathogenic yeast Candida albicans. Infections by the pathogenic yeast Candida albicans are commonly treated with the antifungal agent fluconazole, which inhibits ergosterol biosynthesis. C. albicans can develop resistance to fluconazole by different mechanisms, which often are combined to result in clinically relevant, high-level resistance (20). Besides mutations in the target enzyme that decrease its affinity for the drug, alterations in gene expression are a frequent cause of fluconazole resistance. The constitutive upregulation of ergosterol biosynthesis genes and the overexpression of multidrug efflux pumps of the ABC transporter and major facilitator superfamilies all result in increased azole resistance. Zinc cluster proteins, a family of transcription factors that is unique to the fungal kingdom (17), play a central role in the regulation of genes involved in drug resistance. In C. albicans, Upc2 controls the expression of ergosterol biosynthesis genes (16, 34), Tac1 regulates the expression of the ABC transporters CDR1 and CDR2 (4), and Mrr1 controls the expression of the major facilitator MDR1 (22). These transcription factors mediate the upregulation of their respective target genes in response to inducing stimuli. In addition, gain-of-function mutations in Upc2, Tac1, and Mrr1 result in the constitutive activation of the transcription factors and overexpression of their target genes in fluconazole-resistant strains (1-4, 6, 7, 11, 12, 22, 33, 37). However, it is currently not understood how these transcriptional regulators achieve an activated state under inducing conditions or after the acquisition of gain-offunction mutations.The zinc cluster proteins are defined by a conserved DNA binding motif, which consists of six cysteine residues that coordinate two zinc atoms (Zn 2 Cys 6 ). Most zinc cluster transcription factors have their DNA binding domain at the N terminus, a large negative regulatory domain in the middle of the protein, and an activation domain at the C terminus (17). The transcriptional activity of zinc cluster proteins can be regulated in different ways, but many of them are activated by the binding of inducing molecules (17,23). These can be metabolites, as for transcription factors regulating genes involved in nutrient utilization and biosyntheses (e.g., Put3 and Leu3), or xenobiotics, which activate the pleiotropic drug resistance regulators Pdr1 and Pdr3 in Saccharomyces cerevisiae and Candida glabrata. Pdr1 and Pdr3 are functionally related to Tac1 and Mrr1 of C. albicans, because they also control the expression of multidrug efflux pumps. It has been shown that the binding of drugs and other toxic chemicals to the negative regulatory domain of Pdr1/Pdr3 results in a conformational change that enables the C-terminal activation domain to interact with the...

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“…Cryptococcus neoformans is a pathogenic fungus that causes cryptococcosis in humans (1). C. neoformans is frequently isolated from immunocompromised patients.…”

Section: Introductionmentioning

confidence: 99%