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Antifungal Drugs: The Current Armamentarium and Development of New Agents

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  • Authors: Nicole Robbins1, Gerard D. Wright2, Leah E. Cowen3
  • Editor: Joseph Heitman4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Michael G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; 2: Michael G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; 3: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; 4: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.FUNK-0002-2016
  • Received 01 March 2016 Accepted 20 April 2016 Published 21 October 2016
  • Leah E. Cowen, leah.cowen@utoronto.ca
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  • Abstract:

    Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens , , and collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited. Only three classes of molecules are currently approved for the treatment of invasive mycoses. The efficacy of these agents is compromised by host toxicity, fungistatic activity, or the emergence of drug resistance in pathogen populations. Here we describe our current arsenal of antifungals and highlight current strategies that are being employed to improve the therapeutic safety and efficacy of these drugs. We discuss state-of-the-art approaches to discover novel chemical matter with antifungal activity and highlight some of the most promising new targets for antifungal drug development. We feature the benefits of combination therapy as a strategy to expand our current repertoire of antifungals and discuss the antifungal combinations that have shown the greatest potential for clinical development. Despite the paucity of new classes of antifungals that have come to market in recent years, it is clear that by leveraging innovative approaches to drug discovery and cultivating collaborations between academia and industry, there is great potential to bolster the antifungal armamentarium.

  • Citation: Robbins N, Wright G, Cowen L. 2016. Antifungal Drugs: The Current Armamentarium and Development of New Agents. Microbiol Spectrum 4(5):FUNK-0002-2016. doi:10.1128/microbiolspec.FUNK-0002-2016.

Key Concept Ranking

Fungal Pathogenesis
0.6703879
Fungal Infections
0.6156994
Antifungal Agents
0.6068453
Chemicals
0.5066119
Antifungal Drugs
0.48446766
0.6703879

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/content/journal/microbiolspec/10.1128/microbiolspec.FUNK-0002-2016
2016-10-21
2017-06-25

Abstract:

Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens , , and collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited. Only three classes of molecules are currently approved for the treatment of invasive mycoses. The efficacy of these agents is compromised by host toxicity, fungistatic activity, or the emergence of drug resistance in pathogen populations. Here we describe our current arsenal of antifungals and highlight current strategies that are being employed to improve the therapeutic safety and efficacy of these drugs. We discuss state-of-the-art approaches to discover novel chemical matter with antifungal activity and highlight some of the most promising new targets for antifungal drug development. We feature the benefits of combination therapy as a strategy to expand our current repertoire of antifungals and discuss the antifungal combinations that have shown the greatest potential for clinical development. Despite the paucity of new classes of antifungals that have come to market in recent years, it is clear that by leveraging innovative approaches to drug discovery and cultivating collaborations between academia and industry, there is great potential to bolster the antifungal armamentarium.

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Figures

Image of FIGURE 1
FIGURE 1

Structures and mechanisms of action of clinically relevant antifungal drugs. The azoles function by targeting the ergosterol biosynthetic enzyme lanosterol demethylase, encoded by ( and ) or and (), causing a block in the production of ergosterol and the accumulation of a toxic sterol produced by Erg3. This toxic sterol exerts a severe membrane stress on the cell. Polyenes such as amphotericin B primarily exist in the form of large extramembranous aggregates that extract ergosterol from lipid bilayers. Fungal cell walls are composed of (1,3)-β--glucans covalently linked to (1,6)-β--glucans as well as chitin, mannans, and cell wall proteins. The echinocandins act as noncompetitive inhibitors of (1,3)-β--glucan synthase (encoded by in , , and ) and thereby cause a loss of cell wall integrity and severe cell wall stress. Pyrimidines such as flucytosine become rapidly deaminated in the cytosol to generate 5-fluorouracil (5-FU) by fungal-specific cytosine deaminases. 5-FU acts as a potent antimetabolite that causes RNA miscoding and inhibits DNA synthesis. Adapted from reference 185 with permission.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.FUNK-0002-2016
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Image of FIGURE 2
FIGURE 2

Structures of compounds with antifungal activity. Chemical structures of antifungal molecules highlighted throughout the review. The description in brackets describes the molecular target of the chemical compound.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.FUNK-0002-2016
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