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Antifungal Drug Discovery: Novel Therapies and Approaches
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Antifungal Drug Discovery: Novel Therapies and Approaches

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 19505

Special Issue Editors

Dr. Yanan Zhao

E-Mail Website
Guest Editor
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA
Interests: infectious diseases; medial mycology; molecular diagnostics; antifungal resistance; antibacterial and antifungal drug development; animal models
Dr. Karen Joy Shaw

E-Mail Website
Guest Editor
Hearts Consulting Group, LLC, Poway, CA, USA
Interests: antibacterial and antifungal drug discovery and development; bacteriophage; microbial genetics and physiology; antibiotic resistance; natural product discovery
Dr. James M. Balkovec

E-Mail Website
Guest Editor
Chemtract, LLC, Martinsville, NJ, USA
Interests: medicinal chemistry; organic chemistry; drug discovery; drug development; antifungal; antibacterial; natural products

Special Issue Information

Dear Colleagues,

Invasive fungal infections remain a major cause of global morbidity and mortality, especially in immunocompromised patients with underlying diseases. Despite advances in the treatment of invasive fungal infections over the past several decades, the current antifungal pipeline still requires the identification of safe agents with novel mechanisms of action to address issues of rising resistance and to combat emergent pathogens. In this context, we are calling for studies that focus on exploring novel therapeutic strategies, developing new agents and the discovery of new antifungal targets. For this Special Issue, we welcome reviews and original research articles that cover, but are not limited to, the following topics:

  1. New antifungal agents in preclinical and/or the early phase of clinical development, such as GR-2397, olorofim, novel polyenes, novel cell-wall-active agents, small molecules, natural products, etc.
  2. New strategies/approaches to treat invasive fungal infections, particularly from an immunological perspective.
  3. Novel antifungal targets and their discovery.
  4. PK/PD translation to clinical efficacy.
  5. Combination antifungal therapy.

Dr. Yanan Zhao
Dr. Karen Joy Shaw
Dr. James M. Balkovec
Guest Editors

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 submissions that pass pre-check are 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 monthly 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 2600 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

  • new antifungal agents
  • novel targets
  • immunological approaches
  • PK/PD
  • combination therapy

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Published Papers (6 papers)

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Research

Jump to: Review, Other

20 pages, 1548 KiB  
Article
Clorgyline Analogs Synergize with Azoles against Drug Efflux in Candida auris
by Stephanie Toepfer, Michaela Lackner, Mikhail V. Keniya, Lisa-Maria Zenz, Marianne Friemert, Franz Bracher and Brian C. Monk
J. Fungi 2023, 9(6), 663; https://doi.org/10.3390/jof9060663 - 13 Jun 2023
Cited by 2 | Viewed by 2378
Abstract
Concern about the global emergence of multidrug-resistant fungal pathogens led us to explore the use of combination therapy to combat azole resistance in Candida auris. Clorgyline had previously been shown to be a multi-target inhibitor of Cdr1 and Mdr1 efflux pumps of [...] Read more.
Concern about the global emergence of multidrug-resistant fungal pathogens led us to explore the use of combination therapy to combat azole resistance in Candida auris. Clorgyline had previously been shown to be a multi-target inhibitor of Cdr1 and Mdr1 efflux pumps of Candida albicans and Candida glabrata. A screen for antifungal sensitizers among synthetic analogs of Clorgyline detected interactions with the C. auris efflux pump azole substrates Posaconazole and Voriconazole. Of six Clorgyline analogs, M19 and M25 were identified as potential sensitizers of azole resistance. M19 and M25 were found to act synergistically with azoles against resistant C. auris clade I isolates and recombinant Saccharomyces cerevisiae strains overexpressing C. auris efflux pumps. Nile Red assays with the recombinant strains showed M19 and M25 inhibited the activity of Cdr1 and Mdr1 efflux pumps that are known to play key roles in azole resistance in C. auris clades I, III, and IV. While Clorgyline, M19 and M25 uncoupled the Oligomycin-sensitive ATPase activity of Cdr1 from C. albicans and C. auris, their mode of action is yet to be fully elucidated. The experimental combinations described herein provides a starting point to combat azole resistance dominated by overexpression of CauCdr1 in C. auris clades I and IV and CauMdr1 in C. auris clade III. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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16 pages, 2711 KiB  
Article
Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens
by Sean D. Liston, Luke Whitesell, Mili Kapoor, Karen J. Shaw and Leah E. Cowen
J. Fungi 2022, 8(10), 1102; https://doi.org/10.3390/jof8101102 - 19 Oct 2022
Cited by 4 | Viewed by 2201
Abstract
Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this [...] Read more.
Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1→3)-β-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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Review

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11 pages, 1481 KiB  
Review
Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections
by David A. Angulo, Barbara Alexander, Riina Rautemaa-Richardson, Ana Alastruey-Izquierdo, Martin Hoenigl, Ashraf S. Ibrahim, Mahmoud A. Ghannoum, Thomas R. King, Nkechi E. Azie and Thomas J. Walsh
J. Fungi 2022, 8(11), 1121; https://doi.org/10.3390/jof8111121 - 25 Oct 2022
Cited by 19 | Viewed by 5083
Abstract
Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, [...] Read more.
Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician’s armamentarium against these difficult-to-treat infections. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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31 pages, 6583 KiB  
Review
Guanidine-Containing Antifungal Agents against Human-Relevant Fungal Pathogens (2004–2022)—A Review
by Simon D. P. Baugh
J. Fungi 2022, 8(10), 1085; https://doi.org/10.3390/jof8101085 - 15 Oct 2022
Cited by 3 | Viewed by 2482
Abstract
The guanidine moiety is typically a highly basic group, and can be found in a wide variety of drugs, such as zanamivir (Relenza) and metformin (Fortamet), as well as in biologically active compounds for numerous disease areas, including central nervous system (CNS) diseases [...] Read more.
The guanidine moiety is typically a highly basic group, and can be found in a wide variety of drugs, such as zanamivir (Relenza) and metformin (Fortamet), as well as in biologically active compounds for numerous disease areas, including central nervous system (CNS) diseases and chemotherapeutics. This review will focus on antifungal agents which contain at least one guanidine group, for the treatment of human-related fungal pathogens, described in the literature between 2004 and 2022. These compounds include small molecules, steroids, polymers, metal complexes, sesquiterpenes, natural products, and polypeptides. It shall be made clear that a diverse range of guanidine-containing derivatives have been published in the literature and have antifungal activity, including efficacy in in vivo experiments. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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Other

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9 pages, 444 KiB  
Opinion
Assessment of Antifungal Pharmacodynamics
by Alex Howard and William Hope
J. Fungi 2023, 9(2), 192; https://doi.org/10.3390/jof9020192 - 1 Feb 2023
Cited by 1 | Viewed by 1788
Abstract
Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This [...] Read more.
Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agents. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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11 pages, 672 KiB  
Systematic Review
Recent Antifungal Pipeline Developments against Candida auris: A Systematic Review
by Rogelio de J. Treviño-Rangel, Gloria M. González, Alexandra M. Montoya, Olga C. Rojas, Mariana Elizondo-Zertuche and Neri A. Álvarez-Villalobos
J. Fungi 2022, 8(11), 1144; https://doi.org/10.3390/jof8111144 - 28 Oct 2022
Cited by 10 | Viewed by 4498
Abstract
The alarming spread and impact of multidrug-resistant Candida auris infections alongside the limited therapeutic options have prompted the development of new antifungals. These promising agents are currently in different stages of development, offering novel dosing regimens and mechanisms of action. A systematic search [...] Read more.
The alarming spread and impact of multidrug-resistant Candida auris infections alongside the limited therapeutic options have prompted the development of new antifungals. These promising agents are currently in different stages of development, offering novel dosing regimens and mechanisms of action. A systematic search in MEDLINE, EMBASE, Web of Science, and Scopus up to 27 June 2022 was conducted to find relevant articles reporting data of in vitro activity and in vivo efficacy of investigational antifungals against C. auris. These included new additions to existing antifungal classes (rezafungin and opelconazole), first-in-class drugs such as ibrexafungerp, manogepix/fosmanogepix, olorofim and tetrazoles (quilseconazole, oteseconazole and VT-1598), as well as other innovative agents like ATI-2307, MGCD290 and VL-2397. From 592 articles retrieved in the primary search, 27 met the eligibility criteria. The most studied agent was manogepix/fosmanogepix (overall MIC90: 0.03 mg/L), followed by ibrexafungerp (overall MIC90: 1 mg/L) and rezafungin (overall MIC mode: 0.25 mg/L), while VT-1598 and ATI-2307 were the least explored drugs against C. auris. All these compounds demonstrated significant improvements in survival and reduction in tissue fungal burden on neutropenic animal models of candidemia due to C. auris. Continual efforts towards the discovery of new treatments against this multidrug-resistant fungus are essential. Full article
(This article belongs to the Special Issue Antifungal Drug Discovery: Novel Therapies and Approaches)
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