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Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12719

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Dr. Chi-Ching Tsang

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Guest Editor

School of Medical and Health Sciences, Tung Wah College, Homantin, Hong Kong, China
Interests: medical mycology; emerging infectious diseases; discovery and characterisation of novel pathogens; diagnostic microbiology; antimicrobial susceptibility testing; resistance detection
Special Issues, Collections and Topics in MDPI journals

Dr. Franklin W.N. Chow

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Guest Editor

Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, China
Interests: emerging infectious diseases; host-pathogen interactions; extracellular vesicles; pathogen genomics and evolution; RNA Biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The rise of fungal infections poses an emerging threat to global health. Around 25% of the worldwide population, representing approximately 1.7 billion individuals, suffer from superficial infections of the skin and nails. On top of these, a number of fungal infections can also be deadly. Worryingly, it is estimated that fungal infections kill roughly 1.5 million people each year, and mortality due to invasive fungal diseases is in fact higher than those due to tuberculosis or malaria. However, little is known about the molecular basis of how fungal pathogens cause disease in humans, not to mention about mechanisms leading to antifungal resistance. This severely hampers the development of proper prevention and treatment strategies for combating fungal diseases.

In this Special Issue, we are pleased to invite researchers to contribute a collection of original research and review articles that provide new insights into molecular mechanisms of fungal pathogenesis and antifungal resistance. Topics of interest include, but are not limited to, the following:

Genomics
Transcriptomics
Proteomics
Secretomics
Lipidomics
Metaolomics
Multiomics
Extracellular vesicles
Molecular interactions
Single-cell analyses
Molecular resistance mechanisms

Dr. Chi-Ching Tsang
Dr. Franklin W.N. Chow
Guest Editors

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Keywords

host-fungal interaction
pathogenesis
virulence
antifungal immunity
antifungal resistance

Published Papers (6 papers)

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Research

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15 pages, 1712 KiB

Open AccessArticle

The Transcription Factor StuA Regulates the Glyoxylate Cycle in the Dermatophyte Trichophyton rubrum under Carbon Starvation

by Monise Fazolin Petrucelli, Leonardo Martins-Santana, Pablo R. Sanches, Vanderci M. Oliveira, Antonio Rossi and Nilce M. Martinez-Rossi

Int. J. Mol. Sci. 2024, 25(1), 405; https://doi.org/10.3390/ijms25010405 - 28 Dec 2023

Viewed by 1042

Abstract

Trichophyton rubrum is the primary causative agent of dermatophytosis worldwide. This fungus colonizes keratinized tissues and uses keratin as a nutritional source during infection. In T. rubrum–host interactions, sensing a hostile environment triggers the adaptation of its metabolic machinery to ensure its survival. The glyoxylate cycle has emerged as an alternative metabolic pathway when glucose availability is limited; this enables the conversion of simple carbon compounds into glucose via gluconeogenesis. In this study, we investigated the impact of stuA deletion on the response of glyoxylate cycle enzymes during fungal growth under varying culture conditions in conjunction with post-transcriptional regulation through alternative splicing of the genes encoding these enzymes. We revealed that the ΔstuA mutant downregulated the malate synthase and isocitrate lyase genes in a keratin-containing medium or when co-cultured with human keratinocytes. Alternative splicing of an isocitrate lyase gene yielded a new isoform. Enzymatic activity assays showed specific instances where isocitrate lyase and malate synthase activities were affected in the mutant strain compared to the wild type strain. Taken together, our results indicate a relevant balance in transcriptional regulation that has distinct effects on the enzymatic activities of malate synthase and isocitrate lyase. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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17 pages, 3510 KiB

Open AccessArticle

Trichosporon asahii PLA2 Gene Enhances Drug Resistance to Azoles by Improving Drug Efflux and Biofilm Formation

by Xiaoping Ma, Hong Liu, Zhen Liu, Ya Wang, Zhijun Zhong, Guangneng Peng and Yu Gu

Int. J. Mol. Sci. 2023, 24(10), 8855; https://doi.org/10.3390/ijms24108855 - 16 May 2023

Viewed by 1853

Abstract

Trichosporon asahii is an opportunistic pathogen that can cause severe or even fatal infections in patients with low immune function. sPLA2 plays different roles in different fungi and is also related to fungal drug resistance. However, the mechanism underlying its drug resistance to azoles has not yet been reported in T. asahii. Therefore, we investigated the drug resistance of T. asahii PLA2 (TaPLA2) by constructing overexpressing mutant strains (TaPLA2^OE). TaPLA2^OE was generated by homologous recombination of the recombinant vector pEGFP-N1-TaPLA2, induced by the CMV promoter, with Agrobacterium tumefaciens. The structure of the protein was found to be typical of sPLA2, and it belongs to the phospholipase A2_3 superfamily. TaPLA2^OE enhanced antifungal drug resistance by upregulating the expression of effector genes and increasing the number of arthrospores to promote biofilm formation. TaPLA2^OE was highly sensitive to sodium dodecyl sulfate and Congo red, indicating impaired cell wall integrity due to downregulation of chitin synthesis or degradation genes, which can indirectly affect fungal resistance. In conclusion, TaPLA2 overexpression enhanced the resistance to azoles of T. asahii by enhancing drug efflux and biofilm formation and upregulating HOG-MAPK pathway genes; therefore, it has promising research prospects. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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12 pages, 3539 KiB

Open AccessArticle

Drimane Sesquiterpene Alcohols with Activity against Candida Yeast Obtained by Biotransformation with Cladosporium antarcticum

by Nicole Cortez, Víctor Marín, Verónica A. Jiménez, Víctor Silva, Oscar Leyton, Jaime R. Cabrera-Pardo, Bernd Schmidt, Matthias Heydenreich, Viviana Burgos, Paola Duran and Cristian Paz

Int. J. Mol. Sci. 2022, 23(21), 12995; https://doi.org/10.3390/ijms232112995 - 27 Oct 2022

Viewed by 1627

Abstract

Fungal biotransformation is an attractive synthetic strategy to produce highly specific compounds with chemical functionality in regions of the carbon skeleton that are not easily activated by conventional organic chemistry methods. In this work, Cladosporium antarcticum isolated from sediments of Glacier Collins in Antarctica was used to obtain novel drimane sesquiterpenoids alcohols with activity against Candida yeast from drimendiol and epidrimendiol. These compounds were produced by the high-yield reduction of polygodial and isotadeonal with NaBH₄ in methanol. Cladosporium antarcticum produced two major products from drimendiol, identified as 9α-hydroxydrimendiol (1, 41.4 mg, 19.4% yield) and 3β-hydroxydrimendiol (2, 74.8 mg, 35% yield), whereas the biotransformation of epidrimendiol yielded only one product, 9β-hydroxyepidrimendiol (3, 86.6 mg, 41.6% yield). The products were purified by column chromatography and their structure elucidated by NMR and MS. The antifungal activity of compounds 1–3 was analyzed against Candida albicans, C. krusei and C. parapsilosis, showing that compound 2 has a MIC lower than 15 µg/mL against the three-pathogenic yeast. In silico studies suggest that a possible mechanism of action for the novel compounds is the inhibition of the enzyme lanosterol 14α-demethylase, affecting the ergosterol synthesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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12 pages, 1592 KiB

Open AccessArticle

Drimane Sesquiterpene Aldehydes Control Candida Yeast Isolated from Candidemia in Chilean Patients

by Víctor Marín, Bryan Bart, Nicole Cortez, Verónica A. Jiménez, Víctor Silva, Oscar Leyton, Jaime R. Cabrera-Pardo, Bernd Schmidt, Matthias Heydenreich, Viviana Burgos and Cristian Paz

Int. J. Mol. Sci. 2022, 23(19), 11753; https://doi.org/10.3390/ijms231911753 - 4 Oct 2022

Viewed by 1748

Abstract

Drimys winteri J.R. (Winteraceae) produce drimane sesquiterpenoids with activity against Candida yeast. In this work, drimenol, polygodial (1), isotadeonal (2), and a new drimane α,β-unsaturated 1,4-dialdehyde, named winterdial (4), were purified from barks of D. winteri. The oxidation of drimenol produced the monoaldehyde drimenal (3). These four aldehyde sesquiterpenoids were evaluated against six Candida species isolated from candidemia patients in Chilean hospitals. Results showed that 1 displays fungistatic activity against all yeasts (3.75 to 15.0 µg/mL), but irritant effects on eyes and skin, whereas its non-pungent epimer 2 has fungistatic and fungicide activities at 1.9 and 15.0 µg/mL, respectively. On the other hand, compounds 3 and 4 were less active. Molecular dynamics simulations suggested that compounds 1–4 are capable of binding to the catalytic pocket of lanosterol 14-alpha demethylase with similar binding free energies, thus suggesting a potential mechanism of action through the inhibition of ergosterol synthesis. According to our findings, compound 2 appears as a valuable molecular scaffold to pursue the future development of more potent drugs against candidiasis with fewer side effects than polygodial. These outcomes are significant to broaden the alternatives to treat fungal infections with increasing prevalence worldwide using natural compounds as a primary source for active compounds. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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17 pages, 3244 KiB

Open AccessArticle

The Role of Ergosterol and Sphingolipids in the Localization and Activity of Candida albicans’ Multidrug Transporter Cdr1p and Plasma Membrane ATPase Pma1p

by Aneta K. Urbanek, Jakub Muraszko, Daria Derkacz, Marcin Łukaszewicz, Przemysław Bernat and Anna Krasowska

Int. J. Mol. Sci. 2022, 23(17), 9975; https://doi.org/10.3390/ijms23179975 - 1 Sep 2022

Cited by 7 | Viewed by 2054

Abstract

Opportunistic pathogen Candida albicans causes systemic infections named candidiasis. Due to the increasing number of multi-drug resistant clinical isolates of Candida sp., currently employed antifungals (e.g., azoles) are insufficient for combating fungal infection. One of the resistance mechanisms toward azoles is increased expression of plasma membrane (PM) transporters (e.g., Cdr1p), and such an effect was observed in C. albicans clinical isolates. At the same time, it has been proven that a decrease in PMs sphingolipids (SLs) content correlates with altered sensitivity to azoles and diminished Cdr1p levels. This indicates an important role for SL in maintaining the properties of PM and gaining resistance to antifungal agents. Here, we prove using a novel spot variation fluorescence correlation spectroscopy (svFCS) technique that CaCdr1p localizes in detergent resistant microdomains (DRMs). Immunoblot analysis confirmed the localization of CaCdr1p in DRMs fraction in both the C. albicans WT and erg11Δ/Δ strains after 14 and 24 h of culture. We also show that the C. albicanserg11Δ/Δ strain is more sensitive to the inhibitor of SLs synthesis; aureobasidin A (AbA). AbA treatment leads to a diminished amount of SLs in C. albicans WT and erg11Δ/Δ PM, while, for C. albicanserg11Δ/Δ, the general levels of mannose-inositol-P-ceramide and inositol-P-ceramide are significantly lower than for the C. albicans WT strain. Simultaneously, the level of ergosterol in the C. albicans WT strain after adding of AbA remains unchanged, compared to the control conditions. Analysis of PM permeabilization revealed that treatment with AbA correlates with the disruption of PM integrity in C. albicanserg11Δ/Δ but not in the C. albicans WT strain. Additionally, in the C. albicans WT strain, we observed lower activity of H⁺-ATPase, correlated with the delocalization of both CaCdr1p and CaPma1p. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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Review

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14 pages, 577 KiB

Open AccessReview

The Role of the Glutathione System in Stress Adaptation, Morphogenesis and Virulence of Pathogenic Fungi

by Tanaporn Wangsanut and Monsicha Pongpom

Int. J. Mol. Sci. 2022, 23(18), 10645; https://doi.org/10.3390/ijms231810645 - 13 Sep 2022

Cited by 14 | Viewed by 3330

Abstract

Morphogenesis and stress adaptation are key attributes that allow fungal pathogens to thrive and infect human hosts. During infection, many fungal pathogens undergo morphological changes, and this ability is highly linked to virulence. Furthermore, pathogenic fungi have developed multiple antioxidant defenses to cope with the host-derived oxidative stress produced by phagocytes. Glutathione is a major antioxidant that can prevent cellular damage caused by various oxidative stressors. While the role of glutathione in stress detoxification is known, studies of the glutathione system in fungal morphological switching and virulence are lacking. This review explores the role of glutathione metabolism in fungal adaptation to stress, morphogenesis, and virulence. Our comprehensive analysis of the fungal glutathione metabolism reveals that the role of glutathione extends beyond stressful conditions. Collectively, glutathione and glutathione-related proteins are necessary for vitality, cellular development and pathogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Fungal Pathogenesis and Antifungal Resistance)

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