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Antifungal Drug Discovery: Progresses, Challenges, Opportunities

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

Deadline for manuscript submissions: closed (29 August 2024) | Viewed by 12784

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Dr. Bernhard Biersack

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Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany
Interests: medicinal chemistry; natural products; multi-component reactions; metal-based drugs; antibiotics and antimycotics; anticancer drugs; antiparasitic drugs; antiviral drugs
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Dear Colleagues,

The arsenal of antifungal drugs for the treatment of human mycoses is confined to a few compound classes such as azoles, echinocandines and polyenes, while the eminent health risks based on fungal infections are continuously rising. Immunocompromised people (e.g., elderly people, organ transplantation and cancer patients, persons infected with HIV) especially suffer from life-threatening systemic fungal infections. The formation of drug-resistant pathogenic fungal strains, as well as the emergence of new highly problematic species such as Candida auris, pose a considerable global threat, warranting the development of new and efficient antifungal drug candidates with limited side effects. The severe skin mycoses eumycetoma, chromoblastomycosis and sporotrichosis are classified as neglected tropical diseases (NTDs), with potent antifungals still needing to be discovered and existing drugs being inefficient and often unavailable for patients in rural tropical and subtropical regions.

Thus, new fungicidals with enhanced activity, reduced side effects, and the ability to circumvent drug resistance mechanisms are sought. Promising strategies include the optimization of existing antifungals and the development of first-generation inhibitors of new fungal drug targets. In this regard, the identification and validation of suitable new targets and mechanisms is of high relevance, and these can also include vital interactions of the fungal pathogen with the host. Straightforward formulation and conjugate systems can improve pharmacokinetics and targeting properties. The repurposing of known drugs against other ailments and the rapid and cost-effective application of few-step chemical procedures and multi-component reactions can quickly lead to useful hit compounds.

This Special Issue covers the latest developments and the state of the art of drug design and discovery for the treatment of fungal infections. Original research articles, review articles, perspectives and short communications including (but not restricted to) the described research fields are welcome.

Dr. Bernhard Biersack
Guest Editor

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Keywords

antifungal drugs
fungal infections
drug design
drug discovery
targeted therapy
drug resistance
fungal drug targets
neglected tropical diseases

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Related Special Issue

Antifungal Drug Discovery: Progresses, Challenges, Opportunities, 2nd Edition in International Journal of Molecular Sciences

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Research

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18 pages, 5556 KiB

Open AccessArticle

Ascorbic Acid Enhances the Inhibitory Effect of Theasaponins against Candida albicans

by Yuhong Chen, Ying Gao and Junfeng Yin

Int. J. Mol. Sci. 2024, 25(19), 10661; https://doi.org/10.3390/ijms251910661 - 3 Oct 2024

Viewed by 630

Abstract

Candida albicans (C. albicans) is a main cause of hospital-acquired fungal infections. Combination therapy is promising as a novel anti-C. albicans strategy because of its better efficacy. Theasaponins are pentacyclic triterpenes in the Camellia genus with multiple biological activities. Our previous studies prove that theasaponins display inhibitory activity against C. albicans. Ascorbic acid (VC) is a vitamin found in many plants that shows potential in combination therapy. However, whether VC enhances the activity of theasaponins remains unclear. In this study, the checkerboard micro-dilution method was used to assess the effect of VC (0–80 mmol/L) on the anti-C. albicans effect of theasaponins (0–1000 μg/mL). Then, the effects of theasaponins (31.25 μg/mL), VC (80 mmol/L), and theasaponins (31.25 μg/mL) + VC (80 mmol/L) on C. albicans planktonic cells and different stages of biofilm formation were assessed. Transcriptomic analysis was conducted to investigate the molecular mechanisms. According to the results, VC enhanced the anti-planktonic and anti-biofilm effect of theasaponins against C. albicans. The minimum inhibitory concentration of theasaponins was significantly decreased and the fungicidal efficiency was increased with the addition of VC. VC remarkably aggravated the suppression of theasaponins with regard to various virulence factors of C. albicans, including adhesion, early biofilm formation, mature biofilm, cell surface hydrophobicity, and phospholipase activity. Compared with the theasaponins or VC groups, the level of intracellular reactive oxygen species was higher, while the levels of mitochondrial membrane potential and adenosine triphosphate were lower in the combination group, suggesting more severe oxidative stress, mitochondrial injury, and energy deficiency. Transcriptomic analysis revealed that the combination predominantly suppressed the pathways of glycolysis, glycerophospholipid metabolism, glutathione metabolism, and cysteine and methionine metabolism. This implied that energy deficiency and redox imbalance were associated with the anti-C. albicans activity of the combination. These results prove that VC enhances the inhibitory effect of theasaponins against C. albicans and that the combination has the potential to be used as a topical antifungal therapy or disinfectant. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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33 pages, 8702 KiB

Open AccessArticle

Antifungal Synergy: Mechanistic Insights into the R-1-R Peptide and Bidens pilosa Extract as Potent Therapeutics against Candida spp. through Proteomics

by Yerly Vargas-Casanova, Claudia Patricia Bravo-Chaucanés, Samuel de la Cámara Fuentes, Raquel Martinez-Lopez, Lucía Monteoliva, Concha Gil, Zuly Jenny Rivera-Monroy, Geison Modesti Costa, Javier Eduardo García Castañeda and Claudia Marcela Parra-Giraldo

Int. J. Mol. Sci. 2024, 25(16), 8938; https://doi.org/10.3390/ijms25168938 - 16 Aug 2024

Viewed by 1054

Abstract

Previous reports have demonstrated that the peptide derived from LfcinB, R-1-R, exhibits anti-Candida activity, which is enhanced when combined with an extract from the Bidens pilosa plant. However, the mechanism of action remains unexplored. In this research, a proteomic study was carried out, followed by a bioinformatic analysis and biological assays in both the SC5314 strain and a fluconazole-resistant isolate of Candida albicans after incubation with R-1-R. The proteomic data revealed that treatment with R-1-R led to the up-regulation of most differentially expressed proteins compared to the controls in both strains. These proteins are primarily involved in membrane and cell wall biosynthesis, membrane transport, oxidative stress response, the mitochondrial respiratory chain, and DNA damage response. Additionally, proteomic analysis of the C. albicans parental strain SC5314 treated with R-1-R combined with an ethanolic extract of B. pilosa was performed. The differentially expressed proteins following this combined treatment were involved in similar functional processes as those treated with the R-1-R peptide alone but were mostly down-regulated (data are available through ProteomeXchange with identifier PXD053558). Biological assays validated the proteomic results, evidencing cell surface damage, reactive oxygen species generation, and decreased mitochondrial membrane potential. These findings provide insights into the complex antifungal mechanisms of the R-1-R peptide and its combination with the B. pilosa extract, potentially informing future studies on natural product derivatives. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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13 pages, 3369 KiB

Open AccessArticle

Synergic Effect of the Antimicrobial Peptide ToAP2 and Fluconazole on Candida albicans Biofilms

by Jhones do Nascimento Dias, Fabián Andrés Hurtado Erazo, Lucinda J. Bessa, Peter Eaton, José Roberto de Souza de Almeida Leite, Hugo Costa Paes, André Moraes Nicola, Ildinete Silva-Pereira and Patrícia Albuquerque

Int. J. Mol. Sci. 2024, 25(14), 7769; https://doi.org/10.3390/ijms25147769 - 16 Jul 2024

Viewed by 888

Abstract

Candida albicans is one of the agents of invasive candidiasis, a life-threatening disease strongly associated with hospitalization, particularly among patients in intensive care units with central venous catheters. This study aimed to evaluate the synergistic activity of the antifungal peptide ToAP2 combined with fluconazole against C. albicans biofilms grown on various materials. We tested combinations of different concentrations of the peptide ToAP2 with fluconazole on C. albicans biofilms. These biofilms were generated on 96-well plates, intravenous catheters, and infusion tubes in RPMI medium at two maturation stages. Scanning electron microscopy and atomic force microscopy were employed to assess the biofilm structure. We also evaluated the expression of genes previously proven to be involved in C. albicans biofilm formation in planktonic and biofilm cells after treatment with the peptide ToAP2 using qPCR. ToAP2 demonstrated a synergistic effect with fluconazole at concentrations up to 25 µM during both the early and mature stages of biofilm formation in 96-well plates and on medical devices. Combinations of 50, 25, and 12.5 µM of ToAP2 with 52 µM of fluconazole significantly reduced the biofilm viability compared to individual treatments and untreated controls. These results were supported by substantial structural changes in the biofilms observed through both scanning and atomic force microscopy. The gene expression analysis of C. albicans cells treated with 25 µM of ToAP2 revealed a decrease in the expression of genes associated with membrane synthesis, along with an increase in the expression of genes involved in efflux pumps, adhesins, and filamentation. Our results highlight the efficacy of the combined ToAP2 and fluconazole treatment against C. albicans biofilms. This combination not only shows therapeutic potential but also suggests its utility in developing preventive biofilm tools for intravenous catheters. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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14 pages, 2156 KiB

Open AccessArticle

Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis

by Jingyi Ma, Kimberly Eadie, Marij Schippers, Ahmed Fahal, Benoît Laleu, Annelies Verbon and Wendy W. J. van de Sande

Int. J. Mol. Sci. 2024, 25(11), 6227; https://doi.org/10.3390/ijms25116227 - 5 Jun 2024

Cited by 2 | Viewed by 1027

Abstract

Objectives: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. Methods: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC₅₀ and MIC₅₀ values were obtained. Compounds with an IC₅₀ < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. Results: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. Conclusion: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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19 pages, 8343 KiB

Open AccessArticle

Anti-Biofilm Activity of Assamsaponin A, Theasaponin E1, and Theasaponin E2 against Candida albicans

by Yuhong Chen, Ying Gao, Yifan Li and Junfeng Yin

Int. J. Mol. Sci. 2024, 25(7), 3599; https://doi.org/10.3390/ijms25073599 - 22 Mar 2024

Cited by 1 | Viewed by 1329

Abstract

Biofilm formation plays a crucial role in the pathogenesis of Candida albicans and is significantly associated with resistance to antifungal agents. Tea seed saponins, a class of non-ionic triterpenes, have been proven to have fungicidal effects on planktonic C. albicans. However, their anti-biofilm activity and mechanism of action against C. albicans remain unclear. In this study, the effects of three Camellia sinensis seed saponin monomers, namely, theasaponin E1 (TE1), theasaponin E2 (TE2), and assamsaponin A (ASA), on the metabolism, biofilm development, and expression of the virulence genes of C. albicans were evaluated. The results of the XTT reduction assay and crystal violet (CV) staining assay demonstrated that tea seed saponin monomers concentration-dependently suppressed the adhesion and biofilm formation of C. albicans and were able to eradicate mature biofilms. The compounds were in the following order in terms of their inhibitory effects: ASA > TE1 > TE2. The mechanisms were associated with reductions in multiple crucial virulence factors, including cell surface hydrophobicity (CSH), adhesion ability, hyphal morphology conversion, and phospholipase activity. It was further demonstrated through qRT-PCR analysis that the anti-biofilm activity of ASA and TE1 against C. albicans was attributed to the inhibition of RAS1 activation, which consequently suppressed the cAMP–PKA and MAPK signaling pathways. Conversely, TE2 appeared to regulate the morphological turnover and hyphal growth of C. albicans via a pathway that was independent of RAS1. These findings suggest that tea seed saponin monomers are promising innovative agents against C. albicans. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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Review

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22 pages, 940 KiB

Open AccessReview

Efficacy of Curcumin-Mediated Antimicrobial Photodynamic Therapy on Candida spp.—A Systematic Review

by Magdalena Kubizna, Grzegorz Dawiec and Rafał Wiench

Int. J. Mol. Sci. 2024, 25(15), 8136; https://doi.org/10.3390/ijms25158136 - 26 Jul 2024

Viewed by 2822

Abstract

Oral candidiasis is a common problem among immunocompetent patients. The frequent resistance of Candida strains to popular antimycotics makes it necessary to look for alternative methods of treatment. The authors conducted a systematic review following the PRISMA 2020 guidelines. The objective of this review was to determine if curcumin-mediated blue light could be considered as an alternative treatment for oral candidiasis. PubMed, Google Scholar, and Cochrane Library databases were searched using a combination of the following keywords: (Candida OR candidiasis oral OR candidiasis oral OR denture stomatitis) AND (curcumin OR photodynamic therapy OR apt OR photodynamic antimicrobial chemotherapy OR PACT OR photodynamic inactivation OR PDI). The review included in vitro laboratory studies with Candida spp., in vivo animal studies, and randomized control trials (RCTs) involving patients with oral candidiasis or prosthetic stomatitis, published only in English. The method of elimination of Candida species in the studies was curcumin-mediated aPDT. A total of 757 studies were identified. Following the analysis of the titles and abstracts of the studies, only 42 studies were selected for in-depth screening, after which 26 were included in this study. All studies evaluated the antifungal efficacy of curcumin-mediated aPDT against C. albicans and non-albicans Candida. In studies conducted with planktonic cells solutions, seven studies demonstrated complete elimination of Candida spp. cells. The remaining studies demonstrated only partial elimination. In all cases, experiments on single-species yeast biofilms demonstrated partial, statistically significant inhibition of cell growth and reduction in biofilm mass. In vivo, curcumin-mediated aPDT has shown good antifungal activity against oral candidiasis also in an animal model. However, its clinical efficacy as a potent therapeutic strategy for oral candidiasis requires few further RCTs. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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21 pages, 2552 KiB

Open AccessReview

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

by Bernhard Biersack

Int. J. Mol. Sci. 2024, 25(11), 5977; https://doi.org/10.3390/ijms25115977 - 29 May 2024

Cited by 1 | Viewed by 1734

Abstract

Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development of new efficient drugs, and the emergence of resistant fungal strains. Niclosamide is currently applied for the treatment of worm infections. Its mechanisms of action, which include the suppression of mitochondrial oxidative phosphorylation (also known as mitochondrial uncoupling), among others, has led to a repurposing of this promising anthelmintic drug for the therapy of further human diseases such as cancer, diabetes, and microbial infections. Given the urgent need to develop new drugs against fungal infections, the considerable antifungal properties of niclosamide are highlighted in this review. Its chemical and pharmacological properties relevant for drug development are also briefly mentioned, and the described mitochondria-targeting mechanisms of action add to the current arsenal of approved antifungal drugs. In addition, the activities of further salicylanilide-based niclosamide analogs against fungal pathogens, including agents applied in veterinary medicine for many years, are described and discussed for their feasibility as new antifungals for humans. Preliminary structure–activity relationships are determined and discussed. Various salicylanilide derivatives with antifungal activities showed increased oral bioavailabilities when compared with niclosamide. The simple synthesis of salicylanilide-based drugs also vouchsafes a broad and cost-effective availability for poorer patient groups. Pertinent literature is covered until 2024. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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16 pages, 962 KiB

Open AccessReview

Phytotherapy of Vulvovaginal Candidiasis: A Narrative Review

by Natalia Picheta, Julia Piekarz, Oliwia Burdan, Małgorzata Satora, Rafał Tarkowski and Krzysztof Kułak

Int. J. Mol. Sci. 2024, 25(7), 3796; https://doi.org/10.3390/ijms25073796 - 28 Mar 2024

Cited by 1 | Viewed by 2457

Abstract

Vulvovaginal candidiasis (VVC) is a real gynecological problem among women of reproductive age from 15 to 49. A recent analysis showed that 75% of women will have an occurrence at least once per year, while 5% are observed to have recurrent vaginal mycosis—these patients may become unwell four or more times a year. This pathology is caused in 85–90% of cases by fungi of the Candida albicans species. It represents an intractable medical problem for female patients due to pain and pruritus. Due to the observation of an increasing number of strains resistant to standard preparations and an increase in the recurrence of this pathology when using local or oral preferential therapy, such as fluconazole, an analysis was launched to develop alternative methods of treating VVC using herbs such as dill, turmeric, and berberine. An in-depth analysis of databases that include scientific articles from recent years made it possible to draw satisfactory conclusions supporting the validity of herbal therapy for the pathology in question. Although phytotherapy has not yet been approved by the Food and Drug Administration, it appears to be a promising therapeutic solution for strains that are resistant to existing treatments. There is research currently undergoing aimed at comparing classical pharmacotherapy and herbal therapy in the treatment of vaginal candidiasis for the purpose of increasing medical competence and knowledge for the care of the health and long-term comfort of gynecological patients. Full article

(This article belongs to the Special Issue Antifungal Drug Discovery: Progresses, Challenges, Opportunities)

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