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The Application of Structural Biology in Antifungal Drug Discovery, 2nd...
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The Application of Structural Biology in Antifungal Drug Discovery, 2nd Edition

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungi in Agriculture and Biotechnology".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 6878

Special Issue Editor

Dr. Brian C. Monk

E-Mail Website
Guest Editor
Sir John Walsh Research Institute and Department of Oral Sciences, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand
Interests: mechanisms of antifungal resistance; structural biology of antifungal targets; antifungal drug discovery; yeast biotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The molecular targets of antifungals in clinical and agricultural use or in development include sterol 14α-demethylase (azoles), squalene monooxygenase/epoxidase (allylamines), β1-3 glucan synthase (echinocandins, Ibrexafungerp), ergosterol (polyenes), dihydroorotate dehydrogenase (Olorofim), inositol acyltransferase (Fosmanogepix), thymidylate synthase (pyrimidine analogs), succinate dehydrogenase (SDHIs), complex III (Quinone outside Inhibitors), and tubulins (benzimidazoles). Most of the currently marketed antifungals were discovered without knowledge of the 3-dimensional structure of the target molecule and were improved by establishing structure–activity relationships using phenotypic assays and/or target directed biochemical screens. Where target structures were available, identifying novel antifungal ligands with a suitable clinical window has often proved challenging. Despite this, high-resolution structures of key fungal targets, target–ligand complexes, complexes with structurally related enzymes and even lower resolution structures generated using advances in artificial intelligence can facilitate understanding of resistance mechanisms and drug side-effects, help to improve existing antifungals, and enable identification of novel antifungals using pharmacophore-based discovery or in silico docking of targets with chemically diverse compound libraries and drug-like fragments. This issue extension will address how approaches that incorporate structural biology provide new opportunity for antifungal discovery and development.

Dr. Brian C. Monk
Guest Editor

Manuscript Submission Information

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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.

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Keywords

  • antifungal discovery
  • structural biology
  • drug target structures

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Published Papers (4 papers)

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Research

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27 pages, 6374 KiB  
Article
The Molecular Basis of the Intrinsic and Acquired Resistance to Azole Antifungals in Aspergillus fumigatus
by Parham Hosseini, Mikhail V. Keniya, Alia A. Sagatova, Stephanie Toepfer, Christoph Müller, Joel D. A. Tyndall, Anette Klinger, Edmond Fleischer and Brian C. Monk
J. Fungi 2024, 10(12), 820; https://doi.org/10.3390/jof10120820 - 26 Nov 2024
Viewed by 232
Abstract
Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole [...] Read more.
Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using crystal structures, molecular models, and expression in Saccharomyces cerevisiae of the sterol 14α-demethylase isoforms AfCYP51A and AfCYP51B targeted by azole drugs, together with their cognate reductase AfCPRA2 and AfERG6 (sterol 24-C-methyltransferase). As predicted by molecular modelling, functional expression of CYP51A and B required eburicol and not lanosterol. A crowded conformationally sensitive region involving the BC-loop, helix I, and the heme makes AfCYP51A T289 primarily responsible for resistance to fluconazole, VT-1161, and the agrochemical difenoconazole. The Y121F T289A combination was required for higher level acquired resistance to fluconazole, VT-1161, difenoconazole, and voriconazole, and confirms posaconazole, isavuconazole and possibly ravuconazole as preferred treatments for target-based azole-resistant aspergillosis due to such a combination of mutations. Full article
(This article belongs to the Special Issue The Application of Structural Biology in Antifungal Drug Discovery, 2nd Edition)
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16 pages, 3499 KiB  
Article
Towards a High-Affinity Peptidomimetic Targeting Proliferating Cell Nuclear Antigen from Aspergillus fumigatus
by Bethiney C. Vandborg, Aimee J. Horsfall, Jordan L. Pederick, Andrew D. Abell and John B. Bruning
J. Fungi 2023, 9(11), 1098; https://doi.org/10.3390/jof9111098 - 10 Nov 2023
Viewed by 1358
Abstract
Invasive fungal infections (IFIs) are prevalent in immunocompromised patients. Due to alarming levels of increasing resistance in clinical settings, new drugs targeting the major fungal pathogen Aspergillus fumigatus are required. Attractive drug targets are those involved in essential processes like DNA replication, such [...] Read more.
Invasive fungal infections (IFIs) are prevalent in immunocompromised patients. Due to alarming levels of increasing resistance in clinical settings, new drugs targeting the major fungal pathogen Aspergillus fumigatus are required. Attractive drug targets are those involved in essential processes like DNA replication, such as proliferating cell nuclear antigens (PCNAs). PCNA has been previously studied in cancer research and presents a viable target for antifungals. Human PCNA interacts with the p21 protein, outcompeting binding proteins to halt DNA replication. The affinity of p21 for hPCNA has been shown to outcompete other associating proteins, presenting an attractive scaffold for peptidomimetic design. p21 has no A. fumigatus homolog to our knowledge, yet our group has previously demonstrated that human p21 can interact with A. fumigatus PCNA (afumPCNA). This suggests that a p21-based inhibitor could be designed to outcompete the native binding partners of afumPCNA to inhibit fungal growth. Here, we present an investigation of extensive structure–activity relationships between designed p21-based peptides and afumPCNA and the first crystal structure of a p21 peptide bound to afumPCNA, demonstrating that the A. fumigatus replication model uses a PIP-box sequence as the method for binding to afumPCNA. These results inform the new optimized secondary structure design of a potential peptidomimetic inhibitor of afumPCNA. Full article
(This article belongs to the Special Issue The Application of Structural Biology in Antifungal Drug Discovery, 2nd Edition)
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Review

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13 pages, 4201 KiB  
Review
Fungal Plasma Membrane H+-ATPase: Structure, Mechanism, and Drug Discovery
by Chao-Ran Zhao, Zi-Long You and Lin Bai
J. Fungi 2024, 10(4), 273; https://doi.org/10.3390/jof10040273 - 8 Apr 2024
Viewed by 1640
Abstract
The fungal plasma membrane H+-ATPase (Pma1) pumps protons out of the cell to maintain the transmembrane electrochemical gradient and membrane potential. As an essential P-type ATPase uniquely found in fungi and plants, Pma1 is an attractive antifungal drug target. Two recent [...] Read more.
The fungal plasma membrane H+-ATPase (Pma1) pumps protons out of the cell to maintain the transmembrane electrochemical gradient and membrane potential. As an essential P-type ATPase uniquely found in fungi and plants, Pma1 is an attractive antifungal drug target. Two recent Cryo-EM studies on Pma1 have revealed its hexameric architecture, autoinhibitory and activation mechanisms, and proton transport mechanism. These structures provide new perspectives for the development of antifungal drugs targeting Pma1. In this article, we review the history of Pma1 structure determination, the latest structural insights into Pma1, and drug discoveries targeting Pma1. Full article
(This article belongs to the Special Issue The Application of Structural Biology in Antifungal Drug Discovery, 2nd Edition)
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33 pages, 16136 KiB  
Review
Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights
by Yue Zhou and Todd B. Reynolds
J. Fungi 2024, 10(3), 171; https://doi.org/10.3390/jof10030171 - 22 Feb 2024
Cited by 2 | Viewed by 3162
Abstract
Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially [...] Read more.
Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially ones that contribute to cell wall and cell membrane biosynthesis. Moreover, structural biology has led to a better understanding of the mechanisms by which these enzymes synthesize their products, as well as the mechanism of action for some antifungals. This review summarizes the structures of several current and potential membrane-bound antifungal targets involved in cell wall and cell membrane biosynthesis and their interactions with known inhibitors or drugs. The proposed mechanisms of action for some molecules, gleaned from detailed inhibitor–protein studeis, are also described, which aids in further rational drug design. Furthermore, some potential membrane-bound antifungal targets with known inhibitors that lack solved structures are discussed, as these might be good enzymes for future structure interrogation. Full article
(This article belongs to the Special Issue The Application of Structural Biology in Antifungal Drug Discovery, 2nd Edition)
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