Mitochondria: Gene Lineage, Antifungal Targets and Pathogenesis

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 May 2021) | Viewed by 8972

Special Issue Editor

Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA
Interests: antifungals; drug resistance; bioinformatics; mitochondria
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Journal of Fungi thematic Issue is about mitochondria of fungi. Not all mitochondria are created equally. New insights demonstrate that divergence from common ancestors of ETC complexes I, III, and IV subunit/non-subunit proteins has resulted in three types of alignments. These proteins are either fungal-specific, fungal, algal, and plant-specific, and even lineage-specific proteins. Our thematic Issue will also detail interesting observations on mitochondria in mitophagy, cross-talking of mitochondria and other cell organelles, virulence and pathogenesis, fungal mitochondrial-specific antifungal targets, biogenesis, anti-cell stress activities, metabolism, acetate and mitochondrial stress, and integration of signaling between specific mitochondrial proteins and cell wall synthesis. The thematic issue will include pathogens such as Candida species, Cryptococcus neoformans, Fusarium species (plant and human species), and Aspergillus species.

Prof. Dr. Richard Calderone
Guest Editor

Manuscript Submission Information

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Published Papers (3 papers)

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Research

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18 pages, 3343 KiB  
Article
Antimicrobial Activity of the Peptide LfcinB15 against Candida albicans
by Che-Kang Chang, Mou-Chieh Kao and Chung-Yu Lan
J. Fungi 2021, 7(7), 519; https://doi.org/10.3390/jof7070519 - 29 Jun 2021
Cited by 20 | Viewed by 2654
Abstract
Lactoferricin (Lfcin) is an amphipathic, cationic peptide derived from proteolytic cleavage of the N-lobe of lactoferrin (Lf). Lfcin and its derivatives possess broad-spectrum antibacterial and antifungal activities. However, unlike their antibacterial functions, the modes of action of Lfcin and its derivatives against pathogenic [...] Read more.
Lactoferricin (Lfcin) is an amphipathic, cationic peptide derived from proteolytic cleavage of the N-lobe of lactoferrin (Lf). Lfcin and its derivatives possess broad-spectrum antibacterial and antifungal activities. However, unlike their antibacterial functions, the modes of action of Lfcin and its derivatives against pathogenic fungi are less well understood. In this study, the mechanisms of LfcinB15, a derivative of bovine Lfcin, against Candida albicans were, therefore, extensively investigated. LfcinB15 exhibited inhibitory activity against planktonic cells, biofilm cells, and clinical isolates of C. albicans and non-albicans Candida species. We further demonstrated that LfcinB15 is localized on the cell surface and vacuoles of C. albicans cells. Moreover, LfcinB15 uses several different methods to kill C. albicans, including disturbing the cell membrane, inducing reactive oxygen species (ROS) generation, and causing mitochondrial dysfunction. Finally, the Hog1 and Mkc1 mitogen-activated protein kinases were both activated in C. albicans cells in response to LfcinB15. These findings help us to obtain more insight into the complex mechanisms used by LfcinB15 and other Lfcin-derived peptides to fight fungal pathogens. Full article
(This article belongs to the Special Issue Mitochondria: Gene Lineage, Antifungal Targets and Pathogenesis)
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19 pages, 14027 KiB  
Article
Low Glucose Mediated Fluconazole Tolerance in Cryptococcus neoformans
by Somanon Bhattacharya, Natalia Kronbauer Oliveira, Anne G. Savitt, Vanessa K. A. Silva, Rachel B. Krausert, Berhane Ghebrehiwet and Bettina C. Fries
J. Fungi 2021, 7(6), 489; https://doi.org/10.3390/jof7060489 - 18 Jun 2021
Cited by 5 | Viewed by 3196
Abstract
Chronic meningoencephalitis is caused by Cryptococcus neoformans and is treated in many parts of the world with fluconazole (FLC) monotherapy, which is associated with treatment failure and poor outcome. In the host, C. neoformans propagates predominantly under low glucose growth conditions. We investigated [...] Read more.
Chronic meningoencephalitis is caused by Cryptococcus neoformans and is treated in many parts of the world with fluconazole (FLC) monotherapy, which is associated with treatment failure and poor outcome. In the host, C. neoformans propagates predominantly under low glucose growth conditions. We investigated whether low glucose, mimicked by growing in synthetic media (SM) with 0.05% glucose (SMlowglu), affects FLC-resistance. A > 4-fold increase in FLC tolerance was observed in seven C. neoformans strains when minimum inhibitory concentration (MIC) was determined in SMlowglu compared to MIC in SM with normal (2%) glucose (SMnlglu). In SMlowglu, C. neoformans cells exhibited upregulation of efflux pump genes AFR1 (8.7-fold) and AFR2 (2.5-fold), as well as decreased accumulation (2.6-fold) of Nile Red, an efflux pump substrate. Elevated intracellular ATP levels (3.2-fold and 3.4-fold), as well as decreased mitochondrial reactive oxygen species levels (12.8-fold and 17-fold), were found in the presence and absence of FLC, indicating that low glucose altered mitochondrial function. Fluorescence microscopy revealed that mitochondria of C. neoformans grown in SMlowglu were fragmented, whereas normal glucose promoted a reticular network of mitochondria. Although mitochondrial membrane potential (MMP) was not markedly affected in SMlowglu, it significantly decreased in the presence of FLC (12.5-fold) in SMnlglu, but remained stable in SMlowglu-growing C. neoformans cells. Our data demonstrate that increased FLC tolerance in low glucose-growing C. neoformans is the result of increased efflux pump activities and altered mitochondrial function, which is more preserved in SMlowglu. This mechanism of resistance is different from FLC heteroresistance, which is associated with aneuploidy of chromosome 1 (Chr1). Full article
(This article belongs to the Special Issue Mitochondria: Gene Lineage, Antifungal Targets and Pathogenesis)
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Review

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9 pages, 387 KiB  
Review
Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential
by Nathan P. Wiederhold
J. Fungi 2021, 7(2), 130; https://doi.org/10.3390/jof7020130 - 11 Feb 2021
Cited by 15 | Viewed by 2619
Abstract
Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the [...] Read more.
Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available. Full article
(This article belongs to the Special Issue Mitochondria: Gene Lineage, Antifungal Targets and Pathogenesis)
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