Special Issue "Novel Antifungal Drug Discovery"

A special issue of Journal of Fungi (ISSN 2309-608X).

Deadline for manuscript submissions: closed (16 October 2016).

Special Issue Editor

Prof. Dr. Maurizio Del Poeta
Website
Guest Editor
Department of Microbiology and Immunology, Stony Brook University, 150 Life Science Building, Stony Brook, NY 11794, USA
Interests: novel antifungal development; sphingolipid metabolism and signaling
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Globally, over 300 million people are afflicted by a serious fungal infection and 25 million are at risk of dying or losing their sight. Among fungal infections, invasive infections, such as cryptococcosis, candidiasis, aspergillosis, blastomycosis, histoplasmosis, coccidioidomicosis, and pneumocystosis, are the most common and the most life-threatening. These infections have risen dramatically over the last 20 years, some over 14-fold. Reports from the Center for Disease Control and Prevention (CDC) estimates that over 1,300,000 people are dying every year because of these invasive fungal infections, and, most likely, this is an underestimated figure. This mortality rate is similar to that of malaria (~1,240,000/year) and tuberculosis (~1,400,000/year).

While there are about 30 branded prescription antifungal drugs on the market, three classes of antifungals are mainly used to manage these types of invasive fungal infections: 1) Azoles, such as fluconazole launched in the mid-1980s, 2) polyenes, such as amphotericin B launched in the mid-1950s, and 3) echinocandins, such as caspofungin launched in early 2000.

However, in recent years, the increased use of current azoles has led to an increase in drug resistance, limiting their effectiveness. In addition, drug-drug interaction issues are a major impediment to the use of the azoles voriconazole, itraconazole and posaconazole. Their interactions with cancer chemotherapy agents and immunosuppressants are particularly difficult to handle clinically. Systemic antifungals, such as amphotericin B, tend to have relatively high toxicity and side effects. The echinocandins have a lower incidence of adverse events compared to older antifungals but they bind highly to serum proteins and their antifungal spectrum of activity is very narrow. There is the need for antifungal compounds more effective and safe versus current antifungals.

This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different than the ones of polyenes, azoles, and echinocandins. Authors are specifically chosen as experts in those fields and who are actively researching these topics.

Prof. Dr. Maurizio Del Poeta
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Fungi is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Invasive fungal infections
  • Fungal meningitis
  • Fungal pneumonia
  • Drug resistance
  • Antifungal drugs
  • Cryptococcus neoformans
  • Candida albicans
  • Aspergillus fumigatus
  • Blastomyces dermatitidis
  • Histoplasma capsulatum
  • Coccidioides immitis
  • Pneumocystis jirovecii

Published Papers (5 papers)

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Editorial

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Open AccessEditorial
Special Issue: Novel Antifungal Drug Discovery
J. Fungi 2016, 2(4), 33; https://doi.org/10.3390/jof2040033 - 14 Dec 2016
Cited by 6
Abstract
This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for [...] Read more.
This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for the future development of new antifungal agents to be used alone or in combination with existing antifungals. A computational model for better predicting antifungal drug resistance is also presented. Full article
(This article belongs to the Special Issue Novel Antifungal Drug Discovery)

Research

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Open AccessArticle
A Quantitative Model to Estimate Drug Resistance in Pathogens
J. Fungi 2016, 2(4), 30; https://doi.org/10.3390/jof2040030 - 05 Dec 2016
Cited by 2
Abstract
Pneumocystis pneumonia (PCP) is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, [...] Read more.
Pneumocystis pneumonia (PCP) is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, the primary treatment and prophylaxis for PCP remains a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) that targets two enzymes in folic acid biosynthesis, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), respectively. There is growing evidence of emerging resistance by Pneumocystis jirovecii (the species that infects humans) to TMP-SMX associated with mutations in the targeted enzymes. In the present study, we report the development of an accurate quantitative model to predict changes in the binding affinity of inhibitors (Ki, IC50) to the mutated proteins. The model is based on evolutionary information and amino acid covariance analysis. Predicted changes in binding affinity upon mutations highly correlate with the experimentally measured data. While trained on Pneumocystis jirovecii DHFR/TMP data, the model shows similar or better performance when evaluated on the resistance data for a different inhibitor of PjDFHR, another drug/target pair (PjDHPS/SMX) and another organism (Staphylococcus aureus DHFR/TMP). Therefore, we anticipate that the developed prediction model will be useful in the evaluation of possible resistance of the newly sequenced variants of the pathogen and can be extended to other drug targets and organisms. Full article
(This article belongs to the Special Issue Novel Antifungal Drug Discovery)
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Review

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Open AccessReview
Virulence Factors as Targets for Anticryptococcal Therapy
J. Fungi 2016, 2(4), 29; https://doi.org/10.3390/jof2040029 - 30 Nov 2016
Cited by 11
Abstract
The global mortality due to cryptococcosis caused by Cryptococcus neoformans or C. gattii is unacceptably high. Currently available therapies are decades old and may be impacted by drug resistance. Therefore, the need for more effective antifungal drugs for cryptococcosis is evident. A number [...] Read more.
The global mortality due to cryptococcosis caused by Cryptococcus neoformans or C. gattii is unacceptably high. Currently available therapies are decades old and may be impacted by drug resistance. Therefore, the need for more effective antifungal drugs for cryptococcosis is evident. A number of Cryptococcus virulence factors have been studied in detail, providing crucial information about the fungal biology and putative molecular targets for antifungals. This review focuses on the use of well-described virulence factors of Cryptococcus as potential anticryptococcal agents. Full article
(This article belongs to the Special Issue Novel Antifungal Drug Discovery)
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Open AccessReview
New Horizons in Antifungal Therapy
J. Fungi 2016, 2(4), 26; https://doi.org/10.3390/jof2040026 - 02 Oct 2016
Cited by 66
Abstract
Recent investigations have yielded both profound insights into the mechanisms required by pathogenic fungi for virulence within the human host, as well as novel potential targets for antifungal therapeutics. Some of these studies have resulted in the identification of novel compounds that act [...] Read more.
Recent investigations have yielded both profound insights into the mechanisms required by pathogenic fungi for virulence within the human host, as well as novel potential targets for antifungal therapeutics. Some of these studies have resulted in the identification of novel compounds that act against these pathways and also demonstrate potent antifungal activity. However, considerable effort is required to move from pre-clinical compound testing to true clinical trials, a necessary step toward ultimately bringing new drugs to market. The rising incidence of invasive fungal infections mandates continued efforts to identify new strategies for antifungal therapy. Moreover, these life-threatening infections often occur in our most vulnerable patient populations. In addition to finding completely novel antifungal compounds, there is also a renewed effort to redirect existing drugs for use as antifungal agents. Several recent screens have identified potent antifungal activity in compounds previously indicated for other uses in humans. Together, the combined efforts of academic investigators and the pharmaceutical industry is resulting in exciting new possibilities for the treatment of invasive fungal infections. Full article
(This article belongs to the Special Issue Novel Antifungal Drug Discovery)
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Open AccessReview
Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery
J. Fungi 2016, 2(3), 24; https://doi.org/10.3390/jof2030024 - 06 Sep 2016
Cited by 7
Abstract
Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique [...] Read more.
Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. Cryptococcus neoformans, the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1)-dependent pathway in C. neoformans comprising of sequentially-acting inositol polyphosphate kinases (IPK), which are involved in synthesizing inositol polyphosphates (IP). We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P) and pyrophosphate (PP) groups covalently attached at different positions. This review focuses on (1) the characterization of the Plc1/IPK pathway in C. neoformans; (2) the identification of PP-IP5 (IP7) as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3) why IPK enzymes represent suitable candidates for drug development. Full article
(This article belongs to the Special Issue Novel Antifungal Drug Discovery)
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