Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance

Cowen, Leah E.; Steinbach, William J.

doi:10.1128/ec.00041-08

Cited by 252 publications

(278 citation statements)

References 247 publications

(259 reference statements)

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“…Since Rds2 is a fungal-specific transcription factor that regulates cell wall architecture and pleiotropic drug resistance it could provide a promising drug target. Two-component and phosphorelay signaling systems appear to be absent from mammals and are consequently considered potential drug targets in other fungi and the cell wall synthesis pathway has proven to be a powerful drug target that is being exploited successfully (Hoch 2000;Chauhan and Calderone 2008;Cowen and Steinbach 2008). The identification of a QTN affecting a virulence-related trait furthers our understanding of yeast biology, the evolution of fungal virulence, and how eukaryotic cells cope with imbalances in their redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Survival in a Clinical Saccharomyces cerevisiae Isolate Is Influenced by a Major Quantitative Trait Nucleotide

Diezmann

Dietrich

2011

Genetics

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One of the major challenges in characterizing eukaryotic genetic diversity is the mapping of phenotypes that are the cumulative effect of multiple alleles. We have investigated tolerance of oxidative stress in the yeast Saccharomyces cerevisiae, a trait showing phenotypic variation in the population. Initial crosses identified that this is a quantitative trait. Microorganisms experience oxidative stress in many environments, including during infection of higher eukaryotes. Natural variation in oxidative stress tolerance is an important aspect of response to oxidative stress exerted by the human immune system and an important trait in microbial pathogens. A clinical isolate of the usually benign yeast S. cerevisiae was found to survive oxidative stress significantly better than the laboratory strain. We investigated the genetic basis of increased peroxide survival by crossing those strains, phenotyping 1500 segregants, and genotyping of high-survival segregants by hybridization of bulk and single segregant DNA to microarrays. This effort has led to the identification of an allele of the transcription factor Rds2 as contributing to stress response. Rds2 has not previously been associated with the survival of oxidative stress. The identification of its role in the oxidative stress response here is an example of a specific trait that appears to be beneficial to Saccharomyces cerevisiae when growing as a pathogen. Understanding the role of this fungal-specific transcription factor in pathogenicity will be important in deciphering how fungi infect and colonize the human host and could eventually lead to a novel drug target.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress Survival in a Clinical Saccharomyces cerevisiae Isolate Is Influenced by a Major Quantitative Trait Nucleotide

Diezmann

Dietrich

2011

Genetics

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“…This circuitry enables basal tolerance to azoles, as well as resistance that was acquired by diverse mechanisms (Cowen and Steinbach 2008;Shapiro et al 2011). A leading example of a global cellular regulator that governs stress responses crucial for azole tolerance and resistance is the molecular chaperone Hsp90 (Cowen 2008(Cowen , 2009(Cowen , 2013.…”

Section: Hsp90 and Related Factorsmentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

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471

399

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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“…increasing MICs, any exposure of microorganisms to antimicrobials exerts a stress which is sensed by fungi and to which the microorganism responds in order to survive in a hostile environment. Such sensing and cellular signalling mechanisms contribute as much to antifungal drug-resistance as alterations in the drug target [53,54]. Candida albicans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton rubrum develop compensatory responses related to changes in the cell membrane caused by exposure to sub-inhibitory concentrations of Amphothericin B, Nystatin, Azoles and other drug classes [55][56][57][58][59][60][61][62][63][64][65][66][67].…”

Section: In Vitro Development Of Polyene-resistancementioning

confidence: 99%

“…ergosterol biosynthesis including genes identified as contributing to resistance, but also genes involved in transport, osmotic tolerance, oxidative stress and other genes more. This pleiotropic drug-resistance network contributes to the acquisition of resistance to antifungals beyond structural limits and spanning the fungal kingdoms [53,54].…”

Section: In Vitro Development Of Polyene-resistancementioning

confidence: 99%

For Debate: May the Use of the Polyene Macrolide Natamycin as a Food Additive Foster Emergence of Polyene-Resistance in Candida Species?

Dalhoff¹

2017

Clin Microbiol

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Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance

Cited by 252 publications

References 247 publications

Oxidative Stress Survival in a Clinical Saccharomyces cerevisiae Isolate Is Influenced by a Major Quantitative Trait Nucleotide

Oxidative Stress Survival in a Clinical Saccharomyces cerevisiae Isolate Is Influenced by a Major Quantitative Trait Nucleotide

Mechanisms of Antifungal Drug Resistance

For Debate: May the Use of the Polyene Macrolide Natamycin as a Food Additive Foster Emergence of Polyene-Resistance in Candida Species?

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