Suppression of Sensitivity to Drugs and Antibiotics by High External Cation Concentrations in Fission Yeast

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Abstract

Background

Potassium ion homeostasis plays an important role in regulating membrane potential and therefore resistance to cations, antibiotics and chemotherapeutic agents in Schizosaccharomyces pombe and other yeasts. However, the precise relationship between drug resistance in S. pombe and external potassium concentrations (particularly in its natural habitats) remains unclear. S. pombe can tolerate a wide range of external potassium concentrations which in turn affect plasma membrane polarization. We thus hypothesized that high external potassium concentrations suppress the sensitivity of this yeast to various drugs.

Methods

We have investigated the effect of external KCl concentrations on the sensitivity of S. pombe cells to a wide range of antibiotics, antimicrobial agents and chemotherapeutic drugs. We employed survival assays, immunoblotting and microscopy for these studies.

Results

We demonstrate that KCl, and to a lesser extent NaCl and RbCl can suppress the sensitivity of S. pombe to a wide range of antibiotics. Ammonium chloride and potassium hydrogen sulphate also suppressed drug sensitivity. This effect appears to depend in part on changes to membrane polarization and membrane transport proteins. Interestingly, we have found little relationship between the suppressive effect of KCl on sensitivity and the structure, polarity or solubility of the various compounds investigated.

Conclusions

High concentrations of external potassium and other cations suppress sensitivity to a wide range of drugs in S. pombe. Potassium-rich environments may thus provide S. pombe a competitive advantage in nature. Modulating potassium ion homeostasis may sensitize pathogenic fungi to antifungal agents.

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Most cited references 42

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Regulatory circuitry governing fungal development, drug resistance, and disease.

Rebecca S. Shapiro, Nicole Robbins, Leah E. Cowen (2011)

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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Molecular basis of resistance to azole antifungals.

Antonella Lupetti, Romano Danesi, Mario Campa … (2002)

The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance has prompted investigations of the underlying molecular mechanisms, particularly for the azole compounds central to current therapy. The target site for the azoles is the ERG11 gene product, the cytochrome P450 lanosterol 14alpha-demethylase, which is part of the ergosterol biosynthetic pathway. The resulting ergosterol depletion renders fungal cells vulnerable to further membrane damage. Development of azole resistance in fungi may occur through increased levels of the cellular target, upregulation of genes controlling drug efflux, alterations in sterol synthesis and decreased affinity of azoles for the cellular target. Here, we review the adaptative changes in fungi, in particular Candida albicans, in response to inhibitors of ergosterol biosynthesis. The molecular mechanisms of azole resistance might help in devising more effective antifungal therapies.

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Alkali metal cation transport and homeostasis in yeasts.

Jose M. Ramos, Joaquín Ariño, Hana Sychrová (2010)

The maintenance of appropriate intracellular concentrations of alkali metal cations, principally K(+) and Na(+), is of utmost importance for living cells, since they determine cell volume, intracellular pH, and potential across the plasma membrane, among other important cellular parameters. Yeasts have developed a number of strategies to adapt to large variations in the concentrations of these cations in the environment, basically by controlling transport processes. Plasma membrane high-affinity K(+) transporters allow intracellular accumulation of this cation even when it is scarce in the environment. Exposure to high concentrations of Na(+) can be tolerated due to the existence of an Na(+), K(+)-ATPase and an Na(+), K(+)/H(+)-antiporter, which contribute to the potassium balance as well. Cations can also be sequestered through various antiporters into intracellular organelles, such as the vacuole. Although some uncertainties still persist, the nature of the major structural components responsible for alkali metal cation fluxes across yeast membranes has been defined within the last 20 years. In contrast, the regulatory components and their interactions are, in many cases, still unclear. Conserved signaling pathways (e.g., calcineurin and HOG) are known to participate in the regulation of influx and efflux processes at the plasma membrane level, even though the molecular details are obscure. Similarly, very little is known about the regulation of organellar transport and homeostasis of alkali metal cations. The aim of this review is to provide a comprehensive and up-to-date vision of the mechanisms responsible for alkali metal cation transport and their regulation in the model yeast Saccharomyces cerevisiae and to establish, when possible, comparisons with other yeasts and higher plants.

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Author and article information

Contributors

Juan Mata: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 20 March 2015

Publication date Collection: 2015

Volume: 10

Issue: 3

Electronic Location Identifier: e0119297

Affiliations

[001]Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE-405 30, Göteborg, Sweden

University of Cambridge, UNITED KINGDOM

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: JPA PS. Performed the experiments: JPA AMW AS. Analyzed the data: JPA. Wrote the paper: JPA.

* E-mail: john.p.alao@ 123456cmb.gu.se

Article

Publisher ID: PONE-D-14-34771

DOI: 10.1371/journal.pone.0119297

PMC ID: 4368599

PubMed ID: 25793410

SO-VID: fc30d98e-8e42-4cbf-a112-b00156311e3d

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 2 August 2014

Date accepted : 12 January 2015

Page count

Figures: 6, Tables: 3, Pages: 20

Funding

This work was financially supported by the Swedish Research Council (2010 4645) and the Chemical Biology Platform at the University of Gothenburg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

Suppression of Sensitivity to Drugs and Antibiotics by High External Cation Concentrations in Fission Yeast

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Abstract

Background

Methods

Results

Conclusions

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PLOS Climate

Most cited references 42

Regulatory circuitry governing fungal development, drug resistance, and disease.

Molecular basis of resistance to azole antifungals.

Alkali metal cation transport and homeostasis in yeasts.

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