New Strategies to Combat Human Fungal Infections

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: 31 March 2024 | Viewed by 8556

Special Issue Editors

1. Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
2. Rede Micologia RJ – Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro, Brazil
Interests: chemotherapy; antifungal resistance; biochemistry; cell biology; enzymes; biofilm; virulence
Special Issues, Collections and Topics in MDPI journals
Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Interests: trypanosomatids; biochemistry; enzymes; protease inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last decades, several studies have reported a significant increase in the number of fungal infections worldwide, which result in considerable morbidity and mortality, representing substantial rising costs for the health system. The armamentarium to combat fungal infections is extremely limited considering the few available antifungal drugs and their mechanisms of action, presenting considerable toxicity and several side effects to the host. The seriousness of this situation can be better alleged to fungal infections due to their eukaryote cell architecture and conserved gene sequences closely related to metazoans, including humans, which reflect similarities at both biochemical and immunological levels. Making this scenario worse, antifungal resistance is emerging at a threatening rate and no vaccine is available against fungal infections. Corroborating these statements, the extensive use, misuse and overuse of antimicrobial drugs in treating infectious diseases have led to the emergence of resistance in a wide range of pathogens, including fungi, in a global perspective. Antimicrobial resistance is recognized by the World Health Organization (WHO) as the greatest hazard in the treatment of infectious diseases, which caught the attention of global surveillance authorities and public media to solve this extremely delicate problem.

In recent years, we have seen great improvements in medical practices, which have provided an increase in the survival of hospitalized patients suffering from fungi-related infectious diseases. However, this has also caused an increase in the number of opportunistic, nosocomial and fungal infections. Indeed, many current medical practices are based on procedures that lead to immunosuppression of the patient, such as chemotherapy to treat cancer and organ transplantation. In view of this alarming circumstance, a number of new strategies to combat fungal infections are urgently required. Importantly, novel targets in the fungal cell must be discovered. Furthermore, new bioactive compounds must be synthesized and/or found from different sources. In this context, potential lines of research have been raised: the search for original drugs, the search for potential compounds in public databases and the application of drugs already approved for clinical use for a particular purpose against novel targets (or pathogens). Of particular relevance, novel drugs must be capable of blocking crucial biological events in the fungal cell, leading to growth arrest, inhibition of virulence factors and, most importantly, death. Furthermore, recent advances in combating fungal resistance have focused on the effective combination of two or more antifungals during a treatment regimen or a combination of a classical antifungal agent and a non-antibiotic adjuvant (i.e., a compound that is not fungicidal if administered alone, but is able to increase the activity of the antifungal agent by blocking the target responsible for the mechanism of resistance). In the first approach, antimicrobial combination therapy can be divided into three major categories: (i) inhibition of targets in different pathways; (ii) inhibition of different targets in the same pathway; and (iii) inhibition of the same target in different ways. Therefore, the demand for novel effective antifungal drugs as well as new strategies to combat fungal infections is high and urgently needed.

The Guest Editors invite the international scientific mycological community to contribute works on the abovementioned fields, highlighting the relevant developments of novel antifungal compounds, their mechanisms of action, as well as novel strategies to combat human fungal infections. Both research and review papers in these fields are welcome.

Prof. Dr. André Luis Souza Dos Santos
Prof. Dr. Marta Helena Branquinha
Guest Editors

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Published Papers (6 papers)

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Research

13 pages, 1232 KiB  
Article
Antifungal Activity of Chitosan against Histoplasma capsulatum in Planktonic and Biofilm Forms: A Therapeutic Strategy in the Future?
by Raimunda Sâmia Nogueira Brilhante, Anderson da Cunha Costa, Jacó Ricarte Lima de Mesquita, Gessica dos Santos Araújo, Rosemeyre Souza Freire, João Victor Serra Nunes, Augusto Feynman Dias Nobre, Mirele Rodrigues Fernandes, Marcos Fábio Gadelha Rocha, Waldemiro de Aquino Pereira Neto, Thomas Crouzier, Ulrike Schimpf and Rodrigo Silveira Viera
J. Fungi 2023, 9(12), 1201; https://doi.org/10.3390/jof9121201 - 15 Dec 2023
Viewed by 1174
Abstract
Histoplasmosis is a respiratory disease caused by Histoplasma capsulatum, a dimorphic fungus, with high mortality and morbidity rates, especially in immunocompromised patients. Considering the small existing therapeutic arsenal, new treatment approaches are still required. Chitosan, a linear polysaccharide obtained from partial chitin [...] Read more.
Histoplasmosis is a respiratory disease caused by Histoplasma capsulatum, a dimorphic fungus, with high mortality and morbidity rates, especially in immunocompromised patients. Considering the small existing therapeutic arsenal, new treatment approaches are still required. Chitosan, a linear polysaccharide obtained from partial chitin deacetylation, has anti-inflammatory, antimicrobial, biocompatibility, biodegradability, and non-toxicity properties. Chitosan with different deacetylation degrees and molecular weights has been explored as a potential agent against fungal pathogens. In this study, the chitosan antifungal activity against H. capsulatum was evaluated using the broth microdilution assay, obtaining minimum inhibitory concentrations (MIC) ranging from 32 to 128 µg/mL in the filamentous phase and 8 to 64 µg/mL in the yeast phase. Chitosan combined with classical antifungal drugs showed a synergic effect, reducing chitosan’s MICs by 32 times, demonstrating that there were no antagonistic interactions relating to any of the strains tested. A synergism between chitosan and amphotericin B or itraconazole was detected in the yeast-like form for all strains tested. For H. capsulatum biofilms, chitosan reduced biomass and metabolic activity by about 40% at 512 µg/mL. In conclusion, studying chitosan as a therapeutic strategy against Histoplasma capsulatum is promising, mainly considering its numerous possible applications, including its combination with other compounds. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
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14 pages, 6451 KiB  
Article
Regulatory Ability of Lactiplantibacillus plantarum on Human Skin Health by Counteracting In Vitro Malassezia furfur Effects
by Alessandra Fusco, Brunella Perfetto, Vittoria Savio, Adriana Chiaromonte, Giovanna Torelli, Giovanna Donnarumma and Adone Baroni
J. Fungi 2023, 9(12), 1153; https://doi.org/10.3390/jof9121153 - 29 Nov 2023
Viewed by 1047
Abstract
The skin serves as the first barrier against pathogen attacks, thanks to its multifunctional microbial community. Malassezia furfur is a commensal organism of normal cutaneous microflora but is also a cause of skin diseases. It acts on different cell pattern recognition receptors (TLRs, [...] Read more.
The skin serves as the first barrier against pathogen attacks, thanks to its multifunctional microbial community. Malassezia furfur is a commensal organism of normal cutaneous microflora but is also a cause of skin diseases. It acts on different cell pattern recognition receptors (TLRs, AhR, NLRP3 inflammasome) leading to cellular damage, barrier impairment, and inflammatory cytokines production. Lactobacillus spp. Is an endogenous inhabitant of healthy skin, and studies have proven its beneficial role in wound healing, skin inflammation, and protection against pathogen infections. The aim of our study is to demonstrate the ability of live Lactiplantibacillus plantarum to interfere with the harmful effects of the yeast on human keratinocytes (HaCat) in vitro. To enable this, the cells were treated with M. furfur, either alone or in the presence of L. plantarum. To study the inflammasome activation, cells require a stimulus triggering inflammation (LPS) before M. furfur infection, with or without L. plantarum. L. plantarum effectively counteracts all the harmful strategies of yeast, reducing the phospholipase activity, accelerating wound repair, restoring barrier integrity, reducing AhR and NLRP3 inflammasome activation, and, consequently, releasing inflammatory cytokines. Although lactobacilli have a long history of use in fermented foods, it can be speculated that they can also have health-promoting activities when topically applied. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
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9 pages, 252 KiB  
Communication
The Influence of Medium Composition on EUCAST and Etest Antifungal Susceptibility Testing
by Roya Vahedi-Shahandashti, Melanie Maria Stubenböck and Cornelia Lass-Flörl
J. Fungi 2023, 9(10), 973; https://doi.org/10.3390/jof9100973 - 27 Sep 2023
Viewed by 782
Abstract
There is an ongoing effort to optimize and revise antifungal susceptibility testing (AFST) methods due to the rising number of fungal infections and drug-resistant fungi. The rising antifungal resistance within Candida and Aspergillus species, which are common contributors to invasive fungal infections (IFIs), [...] Read more.
There is an ongoing effort to optimize and revise antifungal susceptibility testing (AFST) methods due to the rising number of fungal infections and drug-resistant fungi. The rising antifungal resistance within Candida and Aspergillus species, which are common contributors to invasive fungal infections (IFIs), is a cause for concern, prompting an expanding integration of in vitro AFST to guide clinical decisions. To improve the relevance of in vitro AFST results to therapy outcomes, influential factors should be taken into account. The tested medium is one of several factors that could affect the results of AFST. The present study evaluated the effect of two complex media (Sabouraud dextrose and Columbia) versus the standard defined medium (RPMI 1640) on the AFST results of amphotericin B, posaconazole, and voriconazole against Candida spp. and Aspergillus spp. representatives, utilizing the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Etest methods. Overall, Candida species exhibited higher variability in minimum inhibitory concentration (MIC) across different media (more than three log2 dilutions) comparing to Aspergillus spp., while quality control isolates showed consistency regardless of tested media, antifungals, and methods. When comparing tested methods, MIC variation was mostly detected using EUCAST than it was using Etest. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
13 pages, 3399 KiB  
Article
Cyclosporine Affects the Main Virulence Factors of Cryptococcus neoformans In Vitro
by Iara Bastos de Andrade, Dario Corrêa-Junior, Vinicius Alves, Maria Helena Galdino Figueiredo-Carvalho, Marcos Vinicius Santos, Marcos Abreu Almeida, Alessandro Fernandes Valdez, Leonardo Nimrichter, Rodrigo Almeida-Paes and Susana Frases
J. Fungi 2023, 9(4), 487; https://doi.org/10.3390/jof9040487 - 18 Apr 2023
Cited by 5 | Viewed by 1195
Abstract
This study aimed to investigate the effects of cyclosporine on the morphology, cell wall structure, and secretion characteristics of Cryptococcus neoformans. The minimum inhibitory concentration (MIC) of cyclosporine was found to be 2 µM (2.4 µg/mL) for the H99 strain. Yeast cells [...] Read more.
This study aimed to investigate the effects of cyclosporine on the morphology, cell wall structure, and secretion characteristics of Cryptococcus neoformans. The minimum inhibitory concentration (MIC) of cyclosporine was found to be 2 µM (2.4 µg/mL) for the H99 strain. Yeast cells treated with cyclosporine at half the MIC showed altered morphology, including irregular shapes and elongated projections, without an effect on cell metabolism. Cyclosporine treatment resulted in an 18-fold increase in chitin and an 8-fold increase in lipid bodies, demonstrating changes in the fungal cell wall structure. Cyclosporine also reduced cell body and polysaccharide capsule diameters, with a significant reduction in urease secretion in C. neoformans cultures. Additionally, the study showed that cyclosporine increased the viscosity of secreted polysaccharides and reduced the electronegativity and conductance of cells. The findings suggest that cyclosporine has significant effects on C. neoformans morphology, cell wall structure, and secretion, which could have implications for the development of new antifungal agents. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
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22 pages, 2472 KiB  
Article
Silver(I) 1,10-Phenanthroline Complexes Are Active against Fonsecaea pedrosoi Viability and Negatively Modulate Its Potential Virulence Attributes
by Ingrid S. Sousa, Tatiana D. P. Vieira, Rubem F. S. Menna-Barreto, Allan J. Guimarães, Pauraic McCarron, Malachy McCann, Michael Devereux, André L. S. Santos and Lucimar F. Kneipp
J. Fungi 2023, 9(3), 356; https://doi.org/10.3390/jof9030356 - 15 Mar 2023
Cited by 3 | Viewed by 1778
Abstract
The genus Fonsecaea is one of the etiological agents of chromoblastomycosis (CBM), a chronic subcutaneous disease that is difficult to treat. This work aimed to evaluate the effects of copper(II), manganese(II) and silver(I) complexes coordinated with 1,10-phenanthroline (phen)/1,10-phenanthroline-5,6-dione (phendione) on Fonsecaea spp. Our [...] Read more.
The genus Fonsecaea is one of the etiological agents of chromoblastomycosis (CBM), a chronic subcutaneous disease that is difficult to treat. This work aimed to evaluate the effects of copper(II), manganese(II) and silver(I) complexes coordinated with 1,10-phenanthroline (phen)/1,10-phenanthroline-5,6-dione (phendione) on Fonsecaea spp. Our results revealed that most of these complexes were able to inhibit F. pedrosoi, F. monophora and F. nubica conidial viability with minimum inhibitory concentration (MIC) values ranging from 0.6 to 100 µM. The most effective complexes against F. pedrosoi planktonic conidial cells, the main etiologic agent of CBM, were [Ag(phen)2]ClO4 and [Ag2(3,6,9-tdda)(phen)4].EtOH, (tdda: 3,6,9-trioxaundecanedioate), displaying MIC values equal to 1.2 and 0.6 µM, respectively. These complexes were effective in reducing the viability of F. pedrosoi biofilm formation and maturation. Silver(I)-tdda-phen, combined with itraconazole, reduced the viability and extracellular matrix during F. pedrosoi biofilm development. Moreover, both silver(I) complexes inhibited either metallo- or aspartic-type peptidase activities of F. pedrosoi as well as its conidia into mycelia transformation and melanin production. In addition, the complexes induced the production of intracellular reactive oxygen species in F. pedrosoi. Taken together, our data corroborate the antifungal action of metal-phen complexes, showing they represent a therapeutic option for fungal infections, including CBM. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
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20 pages, 3976 KiB  
Article
Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box®: In Vitro and In Silico Analyses
by Mariana Ingrid Dutra da Silva Xisto, Rodrigo Rollin-Pinheiro, Yuri de Castro-Almeida, Giulia Maria Pires dos Santos-Freitas, Victor Pereira Rochetti, Luana Pereira Borba-Santos, Yasmin da Silva Fontes, Antonio Ferreira-Pereira, Sonia Rozental and Eliana Barreto-Bergter
J. Fungi 2023, 9(2), 187; https://doi.org/10.3390/jof9020187 - 31 Jan 2023
Cited by 3 | Viewed by 1803
Abstract
Mucormycosis is considered concerning invasive fungal infections due to its high mortality rates, difficult diagnosis and limited treatment approaches. Mucorales species are highly resistant to many antifungal agents and the search for alternatives is an urgent need. In the present study, a library [...] Read more.
Mucormycosis is considered concerning invasive fungal infections due to its high mortality rates, difficult diagnosis and limited treatment approaches. Mucorales species are highly resistant to many antifungal agents and the search for alternatives is an urgent need. In the present study, a library with 400 compounds called the Pandemic Response Box® was used and four compounds were identified: alexidine and three non-commercial molecules. These compounds showed anti-biofilm activity, as well as alterations in fungal morphology and cell wall and plasma membrane structure. They also induced oxidative stress and mitochondrial membrane depolarization. In silico analysis revealed promising pharmacological parameters. These results suggest that these four compounds are potent candidates to be considered in future studies for the development of new approaches to treat mucormycosis. Full article
(This article belongs to the Special Issue New Strategies to Combat Human Fungal Infections)
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