International Journal of Molecular Sciences

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Emerging Antifungal Resistance in Human Pathogenic Fungi

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Prof. Dr. Nir Osherov

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Guest Editor

Sackler Faculty of Medicine, Tel Aviv University, Ramal Aviv 6997801, Israel
Interests: Aspergillus fumigatus virulence factors; development of antifungal drugs

Special Issue Information

Dear Colleagues,

Invasive fungal infections are rapidly increasing due to an expanding population of immunocompromised patients. Only three drug classes of antifungals, the azoles, candins, and polyenes, can be used to treat invasive fungal infections. These drugs have many side effects and fungi are rapidly developing resistance against them. Triazole-resistance has emerged in most pathogenic fungi and has become increasingly widespread. In Aspergillus fumigatus, triazole-resistance in some European countries has dramatically increased from 1% up to 20% from 1999 to 2009. There is also a steady emergence of fluconazole and echinocandin-resistant Candida glabrata and Candida tropicalis isolates, with the highest rates of fluconazole-resistant C. glabrata isolates in North America (10.6%). In addition, the emerging pathogen Candida auris, is intrinsically resistant to fluconazole and 50% of isolates are resistant to two or more classes of antifungals.

For this special issue titled “Emerging Antifungal Resistance in Human Pathogenic Fungi” we encourage the submission of research and review articles on the following topic related to antifungal resistance:

Surveillance and epidemiology of resistance spread.
Mechanisms of resistance, evolution of resistance and effect on virulence.
Overcoming resistance.
Novel antifungal drugs and therapies.

Prof. Dr. Nir Osherov
Guest Editor

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Research

16 pages, 2051 KiB

Open AccessArticle

Alterations in the Level of Ergosterol in Candida albicans’ Plasma Membrane Correspond with Changes in Virulence and Result in Triggering Diversed Inflammatory Response

by Daria Derkacz and Anna Krasowska

Int. J. Mol. Sci. 2023, 24(4), 3966; https://doi.org/10.3390/ijms24043966 - 16 Feb 2023

Cited by 2 | Viewed by 1738

Abstract

Opportunistic pathogen Candida albicans possesses multiple virulence factors which enable colonization and infection of host tissues. Candida-related infections frequently occur in immunocompromised patients, which is related to an insufficient inflammatory response. Furthermore, immunosuppression and multidrug resistance of C. albicans clinical isolates make the treatment of candidiasis a challenge for modern medicine. The most common resistance mechanism of C. albicans to antifungals includes point mutations in the ERG11 gene, which encodes target protein for azoles. We investigated whether the mutations or deletion of the ERG11 gene influence the pathogen-host interactions. We prove that both C. albicans erg11∆/∆ and ERG11K143R/K143R exhibit increased cell surface hydrophobicity. Additionally, C. albicans KS058 has an impaired ability of biofilm and hyphae formation. Analysis of the inflammatory response of human dermal fibroblasts and vaginal epithelial cell lines revealed that altered morphology of C. albicans erg11∆/∆ results in a significantly weaker immune response. C. albicans ERG11K143R/K143R triggered stronger production of pro-inflammatory response. Analysis of genes encoding adhesins confirmed differences in the expression pattern of key adhesins for both erg11∆/∆ and ERG11K143R/K143R strains. Obtained data indicate that alterations in Erg11p consequence in resistance to azoles and affect the key virulence factors and inflammatory response of host cells. Full article

(This article belongs to the Special Issue Emerging Antifungal Resistance in Human Pathogenic Fungi)

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12 pages, 3878 KiB

Open AccessArticle

Identification and Analysis of Fungal-Specific Regions in the Aspergillus fumigatus Cu Exporter CrpA That Are Essential for Cu Resistance but Not for Virulence

by Hila Werner, Ammar Abou Kandil, Zohar Meir, Yehonathan Malis, Yona Shadkchan, Gal Masrati, Nir Ben-Tal, Koret Hirschberg and Nir Osherov

Int. J. Mol. Sci. 2023, 24(4), 3705; https://doi.org/10.3390/ijms24043705 - 13 Feb 2023

Cited by 1 | Viewed by 1551

Abstract

The opportunistic fungus Aspergillus fumigatus is the primary invasive mold pathogen in humans, and is responsible for an estimated 200,000 yearly deaths worldwide. Most fatalities occur in immunocompromised patients who lack the cellular and humoral defenses necessary to halt the pathogen’s advance, primarily in the lungs. One of the cellular responses used by macrophages to counteract fungal infection is the accumulation of high phagolysosomal Cu levels to destroy ingested pathogens. A. fumigatus responds by activating high expression levels of crpA, which encodes a Cu⁺ P-type ATPase that actively transports excess Cu from the cytoplasm to the extracellular environment. In this study, we used a bioinformatics approach to identify two fungal-unique regions in CrpA that we studied by deletion/replacement, subcellular localization, Cu sensitivity in vitro, killing by mouse alveolar macrophages, and virulence in a mouse model of invasive pulmonary aspergillosis. Deletion of CrpA fungal-unique amino acids 1–211 containing two N-terminal Cu-binding sites, moderately increased Cu-sensitivity but did not affect expression or localization to the endoplasmic reticulum (ER) and cell surface. Replacement of CrpA fungal-unique amino acids 542–556 consisting of an intracellular loop between the second and third transmembrane helices resulted in ER retention of the protein and strongly increased Cu-sensitivity. Deleting CrpA N-terminal amino acids 1–211 or replacing amino acids 542–556 also increased sensitivity to killing by mouse alveolar macrophages. Surprisingly, the two mutations did not affect virulence in a mouse model of infection, suggesting that even weak Cu-efflux activity by mutated CrpA preserves fungal virulence. Full article

(This article belongs to the Special Issue Emerging Antifungal Resistance in Human Pathogenic Fungi)

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