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Design and Mechanism of Action of Genomic-Based Antifungals
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Design and Mechanism of Action of Genomic-Based Antifungals

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Genomics, Genetics and Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 6763

Special Issue Editors

Prof. Dr. Everardo López-Romero

E-Mail Website
Guest Editor
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato 36050, Mexico
Interests: fungal physiology and metabolism
Prof. Dr. Mayra Cuéllar-Cruz

E-Mail Website
Guest Editor
Department of Biology, University of Guanajuato, Guanajuato 36050, Mexico
Interests: biomineralization; inorganic crystals; crystal growth; biocrystals; biological macromolecules

Special Issue Information

Dear Colleagues,

The last fifty years have witnessed an increasing number of human diseases caused by pathogenic fungi, particularly in hospitalized patients and those with suppressed or dejected immune systems. This has converted fungal diseases into a serious threat to public health around the world. A major problem of fungal infections is that the amount of available antifungals is rather limited, particularly for the treatment of life-threatening invasive, serious mycosis. Some examples include traditional amphothericin B and its lipidic formulations, an efficient but toxic antifungal. Fortunately, less toxic and more potent drugs have been developed as primary alternative options for the treatment of fungal diseases. These include the semisynthetic echinocandins (caspafungin, micafungin, and anidulafungin) that function as inhibitors of b1-3 glucan synthetase, an essential enzyme involved in fungal cell wall biosynthesis, as well as the azoles (fluconazol, voriconazol, itraconazol, isavuconozol, and posaconazol) that block ergosterol synthesis and flucytosine, an inhibitor of cell replication.

Molecular biology offers a number of promising possibilities for the development of, ideally, more specific and potent antifungals. Knowledge of the 3D structures of genes, regulators of gene expression, transcripts, proteins, and, in general, all genome elements involved in fungal pathogenicity and virulence may serve to configure antagonic structures that may serve as antifungals for the treatment of common infections caused by pathogens such as Candida, Aspergillus, Cryptococcus, Hystoplasma, Blastomyces, Mucor, Sporothrix, and others.

This Special Issue deals with efforts and communications of molecular biology-based approaches to design antimycotic drugs to prevent and cure disseminated mycoses.

Prof. Dr. Everardo López-Romero
Prof. Dr. Mayra Cuéllar-Cruz
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

  • fungal diseases
  • life-threating mycoses
  • traditional antimycotic drugs
  • toxicity
  • modified antifungals
  • genomic-based design antifungals
  • structure
  • mechanism of action
  • selectivity specificity
  • efficiency

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Published Papers (5 papers)

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Research

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15 pages, 4624 KiB  
Article
Antifungal Efficacy of Luliconazole-Loaded Nanostructured Lipid-Carrier Gel in an Animal Model of Dermatophytosis
by Robab Ebrahimi Barogh, Seyyed Mobin Rahimnia, Mohsen Nosratabadi, Abolfazl Maleki, Fatemeh Khosravi Ebrahimi, Zahra Yahyazade, Iman Haghani, Pedram Ebrahimnejad, Majid Saeedi, Darius Armstrong-James, Mahdi Abastabar and Hamid Badali
J. Fungi 2025, 11(4), 324; https://doi.org/10.3390/jof11040324 - 19 Apr 2025
Viewed by 164
Abstract
Background: Trichophyton indotineae terbinafine-resistant infections are emerging in healthy individuals. Luliconazole, an imidazole antifungal that is effective against skin infections, faces challenges due to low water solubility and poor skin penetration. This study aimed to formulate a luliconazole-loaded nanostructured lipid-carrier (NLC) gel [...] Read more.
Background: Trichophyton indotineae terbinafine-resistant infections are emerging in healthy individuals. Luliconazole, an imidazole antifungal that is effective against skin infections, faces challenges due to low water solubility and poor skin penetration. This study aimed to formulate a luliconazole-loaded nanostructured lipid-carrier (NLC) gel in a Carbopol-based system to enhance drug absorption and efficacy in a guinea pig model of dermatophytosis. Methods: Luliconazole-loaded nanostructured lipid carriers (NLCs) were prepared using a solvent evaporation method and gel formulation. Skin absorption and retention were assessed via Franz diffusion cells. The antifungal efficacy was tested against T. indotineae in thirty guinea pigs with induced tinea corporis, divided into five treatment groups. Mycological, clinical, and histopathological evaluations were conducted, along with skin irritation studies for safety. Results: LCZ-NLC demonstrated significantly better skin penetration than simple luliconazole gel, with cumulative drug penetration of 71.8 ± 3.7 μg/cm2 versus 50.9 ± 4.2 μg/cm2 after 24 h. Both formulations achieved complete infection resolution after 21 and 28 days, with reduced inflammation and no local irritations. On day 21, the LCZ-NLC 1% gel significantly reduced lesion scores and mycological evidence of infection compared to the terbinafine-treated groups, untreated controls, and NLC-gel-treated group (p < 0.05). Histopathological analysis indicated a reduction in both epidermal thickening and fungal burden in the models that received treatment with the LCZ-NLC 1% gel. Conclusions: Luliconazole-loaded lipid carriers enhance drug absorption and efficacy, suggesting shorter treatment durations and improved patient outcomes for resistant fungal infections. However, further studies are warranted to correlate these findings with clinical outcomes. Full article
(This article belongs to the Special Issue Design and Mechanism of Action of Genomic-Based Antifungals)
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14 pages, 635 KiB  
Article
In Vitro Assessment of Fluconazole and Cyclosporine A Antifungal Activities: A Promising Drug Combination Against Different Candida Species
by Juan Daniel Carton, Iñigo de-la-Fuente, Elena Sevillano, Nerea Jauregizar, Guillermo Quindós, Elena Eraso and Andrea Guridi
J. Fungi 2025, 11(2), 133; https://doi.org/10.3390/jof11020133 - 10 Feb 2025
Viewed by 887
Abstract
Invasive candidiasis is a common fungal infection associated with multiple risk factors, such as cancer, neutropenia, corticosteroid therapy, catheterization, and the use of broad-spectrum antibiotic treatment. Candida albicans is the predominant causative agent, although other Candida species have been emerging in the last [...] Read more.
Invasive candidiasis is a common fungal infection associated with multiple risk factors, such as cancer, neutropenia, corticosteroid therapy, catheterization, and the use of broad-spectrum antibiotic treatment. Candida albicans is the predominant causative agent, although other Candida species have been emerging in the last years, together with a rise in a number of strains resistant to the currently available antifungal drugs, which poses a challenge when treating these infections. Drug repurposing and drug combinations are promising strategies for the treatment of invasive mycoses. In this study, we evaluated the effect of the combination of fluconazole (FLZ) and cyclosporine A (CsA) against 39 clinical isolates and reference strains of Candida. Two methods, the Loewe additivity model and Bliss independence model, were used to assess the antifungal activity of the drug combination according to CLSI and EUCAST guidelines. The results demonstrated a synergistic effect between fluconazole (FLZ) and cyclosporine A (CsA) against 15–17 Candida isolates, depending on the evaluation model used, including FLZ-resistant strains of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. Notably, the combination significantly reduced the minimum inhibitory concentration (MIC) of FLZ in a substantial number of isolates, including those with resistance to FLZ. Additionally, time–kill curve studies confirmed the synergistic interaction, further validating the potential of this combination as an alternative therapeutic strategy for candidiasis treatment. These findings emphasize the importance of investigating innovative drug combinations to address the challenges posed by antifungal resistance and improve treatment options for invasive fungal infections. Full article
(This article belongs to the Special Issue Design and Mechanism of Action of Genomic-Based Antifungals)
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22 pages, 5876 KiB  
Article
Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of Candida albicans
by Bhabasha Gyanadeep Utkalaja, Satya Ranjan Sahu, Sushree Subhashree Parida and Narottam Acharya
J. Fungi 2024, 10(3), 222; https://doi.org/10.3390/jof10030222 - 19 Mar 2024
Cited by 4 | Viewed by 2312
Abstract
The incidence of infections caused by Candida species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. [...] Read more.
The incidence of infections caused by Candida species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of C. albicans that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in C. albicans rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy. Full article
(This article belongs to the Special Issue Design and Mechanism of Action of Genomic-Based Antifungals)
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Review

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17 pages, 1317 KiB  
Review
Molecular Mechanisms of Pathogenic Fungal Virulence Regulation by Cell Membrane Phospholipids
by Yitong Li, Hongchen Wang, Hengxiu Wang, Tianming Wang, Daqiang Wu and Wenfan Wei
J. Fungi 2025, 11(4), 256; https://doi.org/10.3390/jof11040256 - 26 Mar 2025
Viewed by 399
Abstract
Pathogenic fungi represent a growing concern for human health, necessitating a deeper understanding of their molecular mechanisms of virulence to formulate effective antifungal strategies. Recent research has increasingly highlighted the role of phospholipid components in fungal cell membranes, which are not only vital [...] Read more.
Pathogenic fungi represent a growing concern for human health, necessitating a deeper understanding of their molecular mechanisms of virulence to formulate effective antifungal strategies. Recent research has increasingly highlighted the role of phospholipid components in fungal cell membranes, which are not only vital for maintaining cellular integrity but also significantly influence fungal pathogenicity. This review focuses on the impact of membrane phospholipid composition on fungal growth, morphogenesis, stress responses, and interactions with host cells. To be specific, membrane phospholipid composition critically influences fungal virulence by modulating growth dynamics and morphogenesis, such as the transition from yeast to hyphal forms, which enhances tissue invasion. Additionally, phospholipids mediate stress adaptation, enabling fungi to withstand host-derived oxidative and osmotic stresses, crucial for survival within hostile host environments. Phospholipid asymmetry also impacts interactions with host cells, including adhesion, phagocytosis evasion, and the secretion of virulence factors like hydrolytic enzymes. These adaptations collectively enhance fungal pathogenicity by promoting colonization, immune evasion, and damage to host tissues, directly linking membrane architecture to infection outcomes. By elucidating the molecular mechanisms involved, we aim to underscore the potential of targeting phospholipid metabolic pathways as a promising avenue for antifungal therapy. A comprehensive understanding of how membrane phospholipid composition regulates the virulence of pathogenic fungi can provide valuable insights for developing novel antifungal strategies. Full article
(This article belongs to the Special Issue Design and Mechanism of Action of Genomic-Based Antifungals)
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25 pages, 2086 KiB  
Review
New Ground in Antifungal Discovery and Therapy for Invasive Fungal Infections: Innovations, Challenges, and Future Directions
by Gustavo A. Niño-Vega, Leonardo Padró-Villegas and Everardo López-Romero
J. Fungi 2024, 10(12), 871; https://doi.org/10.3390/jof10120871 - 15 Dec 2024
Cited by 1 | Viewed by 2298
Abstract
This review explores current advancements and challenges in antifungal therapies amid rising fungal infections, particularly in immunocompromised patients. We detail the limitations of existing antifungal classes—azoles, echinocandins, polyenes, and flucytosine—in managing systemic infections and the urgent need for alternative solutions. With the increasing [...] Read more.
This review explores current advancements and challenges in antifungal therapies amid rising fungal infections, particularly in immunocompromised patients. We detail the limitations of existing antifungal classes—azoles, echinocandins, polyenes, and flucytosine—in managing systemic infections and the urgent need for alternative solutions. With the increasing incidence of resistance pathogens, such as Candida auris and Aspergillus fumigatus, we assess emerging antifungal agents, including Ibrexafungerp, T-2307, and N′-Phenylhydrazides, which target diverse fungal cell mechanisms. Innovations, such as nanoparticles, drug repurposing, and natural products, are also evaluated for their potential to improve efficacy and reduce resistance. We emphasize the importance of novel approaches to address the growing threat posed by fungal infections, particularly for patients with limited treatment options. Finally, we briefly examine the potential use of artificial intelligence (AI) in the development of new antifungal treatments, diagnoses, and resistance prediction, which provides powerful tools in the fight against fungal pathogens. Overall, we highlight the pressing need for continued research to advance antifungal treatments and improve outcomes for high-risk populations. Full article
(This article belongs to the Special Issue Design and Mechanism of Action of Genomic-Based Antifungals)
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