Anticapsular and Antifungal Activity of α-Cyperone

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens.

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Impact of antifungal resistance in Australia

Microbiology Australia ◽

10.1071/ma07171 ◽

2007 ◽

Vol 28 (4) ◽

pp. 174 ◽

Cited By ~ 5

Author(s):

David Ellis ◽

Tania Sorrell ◽

Sharon Chen

Keyword(s):

Antifungal Activity ◽

Selection Pressure ◽

Opportunistic Infections ◽

Fungal Infections ◽

Fungal Species ◽

Antifungal Drugs ◽

Drug Resistant ◽

Populations At Risk ◽

Complete Resistance ◽

Major Increase

The last two to three decades have seen a major increase in invasive fungal infections (IFIs), a small, but increasing proportion of which are caused by pathogens with partial or complete resistance to antifungal drugs. The increase in IFIs has largely been associated with the increase in immunocompromised and critically ill patients. Opportunistic infections with relatively drug-resistant environmental fungi account for much of the resistance. In addition, amongst the only fungal species to colonise humans, Candida, two species that are resistant (C. krusei) or relatively resistant (C. glabrata) to fluconazole have emerged. In part this is explained by the selection pressure exerted by widespread use of fluconazole. Together with the introduction of new antifungal drugs with selective and/or variable antifungal activity, these changes have stimulated interest in understanding mechanisms and origins of resistance, the identification of resistance in the laboratory and its relationship to clinical outcomes, and in surveillance of clinical isolates and populations at risk of IFIs.

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Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

Microorganisms ◽

10.3390/microorganisms9030500 ◽

2021 ◽

Vol 9 (3) ◽

pp. 500 ◽

Cited By ~ 1

Author(s):

Priyanka Bapat ◽

Gurbinder Singh ◽

Clarissa J. Nobile

Keyword(s):

Candida Albicans ◽

Photodynamic Therapy ◽

Biofilm Formation ◽

Fungal Pathogens ◽

Fungal Infections ◽

Therapeutic Strategies ◽

Antifungal Drugs ◽

Clinical Settings ◽

Drug Resistant ◽

Candida Albicans Biofilms

Fungal infections are increasing in prevalence worldwide, especially in immunocompromised individuals. Given the emergence of drug-resistant fungi and the fact that there are only three major classes of antifungal drugs available to treat invasive fungal infections, there is a need to develop alternative therapeutic strategies effective against fungal infections. Candida albicans is a commensal of the human microbiota that is also one of the most common fungal pathogens isolated from clinical settings. C. albicans possesses several virulence traits that contribute to its pathogenicity, including the ability to form drug-resistant biofilms, which can make C. albicans infections particularly challenging to treat. Here, we explored red, green, and blue visible lights alone and in combination with common photosensitizing compounds for their efficacies at inhibiting and disrupting C. albicans biofilms. We found that blue light inhibited biofilm formation and disrupted mature biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential. Red and green lights, however, inhibited biofilm formation only in combination with photosensitizing compounds but had no effects on disrupting mature biofilms. Taken together, these results suggest that photodynamic therapy may be an effective non-drug treatment for fungal biofilm infections that is worthy of further exploration.

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Alexidine dihydrochloride has broad spectrum a ctivities against diverse fungal pathogens

10.1101/429944 ◽

2018 ◽

Author(s):

Zeinab Mamouei ◽

Abdullah Alqarihi ◽

Shakti Singh ◽

Shuying Xu ◽

Michael K. Mansour ◽

...

Keyword(s):

Mammalian Cell ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Drugs ◽

Immunocompromised Patients ◽

Drug Resistant ◽

Cell Toxicity ◽

Diverse Range ◽

Mammalian Cell Toxicity

AbstractInvasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, constitute a substantial threat to hospitalized, immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices, and emergence of drug-resistant fungi such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms which increases the chance of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens, and their ability to kill preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.ImportanceThe prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multi-drug resistant strains such as C. auris. High mortality related to fungal infections point to major limitations of current antifungal therapy, and an unmet need for new antifungal drugs. We screened a library of repurposed FDA approved inhibitors to identify compounds with activities against a diverse range of fungi, in varied phases of growth. The assays identified Alexidine dihydrochloride (AXD) to have pronounced antifungal activity including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro, and prevented biofilm growth in vivo. Thus AXD has the potential to be developed as a pan-antifungal, anti-biofilm drug.

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Recent Advances in Azole Based Scaffolds as Anticandidal Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180917125916 ◽

2019 ◽

Vol 16 (5) ◽

pp. 492-501 ◽

Cited By ~ 1

Author(s):

Prabhuodeyara Math Gurubasavaraj ◽

Jasmith Shivayya Charantimath

Keyword(s):

Drug Delivery ◽

Drug Resistance ◽

Candida Albicans ◽

Drug Interactions ◽

Fungal Pathogens ◽

Antifungal Agents ◽

Fungal Infections ◽

Antifungal Drugs ◽

Fungal Virulence ◽

Compromised Patients

Aim:The present review aims to explore the development of novel antifungal agents, such as pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and other aspects that involve drug-drug interactions of the azole antifungal agents.Introduction:Fungal infections in critically ill and immune-compromised patients are increasing at alarming rates, caused mainly by Candida albicans an opportunistic fungus. Despite antifungal annihilators like amphotericin B, azoles and caspofungin, these infections are enormously increasing. The unconventional increase in such patients is a challenging task for the management of antifungal infections especially Candidiasis. Moreover, problem of toxicity associated with antifungal drugs on hosts and rise of drug-resistance in primary and opportunistic fungal pathogens has obstructed the success of antifungal therapy.Conclusion:Hence, to conflict these problems new antifungal agents with advanced efficacy, new formulations of drug delivery and novel compounds which can interact with fungal virulence are developed and used to treat antifungal infections.

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Novel Hit Compounds as Putative Antifungals: The Case of Aspergillus fumigatus

Molecules ◽

10.3390/molecules24213853 ◽

2019 ◽

Vol 24 (21) ◽

pp. 3853 ◽

Cited By ~ 5

Author(s):

Eftichia Kritsi ◽

Minos-Timotheos Matsoukas ◽

Constantinos Potamitis ◽

Anastasia Detsi ◽

Marija Ivanov ◽

...

Keyword(s):

Antifungal Activity ◽

Aspergillus Fumigatus ◽

Fungal Pathogens ◽

Fungal Infections ◽

Pharmacophore Model ◽

Antifungal Drugs ◽

In Vitro Assays ◽

Minimum Fungicidal Concentration ◽

Dynamics Simulations

The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely used category for the treatment of fungal infections. However, increasingly, azole-resistant strains constitute a major problem to be faced. Towards this direction, our study focused on the identification of compounds bearing novel structural motifs which may evolve as a new class of antifungals. To fulfil this scope, a combination of in silico techniques and in vitro assays were implemented. Specifically, a ligand-based pharmacophore model was created and served as a 3D search query to screen the ZINC chemical database. Additionally, molecular docking and molecular dynamics simulations were used to improve the reliability and accuracy of virtual screening results. In total, eight compounds, bearing completely different chemical scaffolds from the commercially available azoles, were proposed and their antifungal activity was evaluated using in vitro assays. Results indicated that all tested compounds exhibit antifungal activity, especially compounds 1, 2, and 4, which presented the most promising minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values and, therefore, could be subjected to further hit to lead optimization.

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Drug Repurposing Strategies in the Discovery of Antifungal Agents

10.20944/preprints202102.0405.v1 ◽

2021 ◽

Author(s):

Qian Zhang ◽

Fangyan Liu ◽

Meng Zeng ◽

Caiyan Xin ◽

Jinping Zhang ◽

...

Keyword(s):

Antifungal Activity ◽

Clinical Application ◽

Antifungal Agents ◽

Fungal Infections ◽

Immunosuppressive Agents ◽

Drug Repurposing ◽

Antifungal Drugs ◽

Drug Resistant ◽

Effective Strategies ◽

Prevention And Treatment

The morbidity and mortality caused by invasive fungal infections is increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is an effective way of expanding the application of existing drugs. In the last years, various existing drugs have been shown to be useful in the prevention and treatment of the invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up to date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field.

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Catalytic defense against fungal pathogens using nanozymes

Nanotechnology Reviews ◽

10.1515/ntrev-2021-0084 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1277-1292

Author(s):

Wu Qingzhi ◽

Sijia Zou ◽

Qian Wang ◽

Lei Chen ◽

Xiyun Yan ◽

...

Keyword(s):

Fungal Pathogens ◽

Fungal Infections ◽

Low Cost ◽

Enzymatic Catalysis ◽

Antifungal Drugs ◽

Drug Resistant ◽

Enzyme Mimics ◽

Artificial Enzyme ◽

Promising Alternative ◽

Promising Strategy

Abstract Fungal infections are still a major challenge for clinics, resulting from the resistance of drug-resistant fungi and the toxicity of antifungal drugs. Defense against fungal invasions via enzymatic catalysis has been found in nature. The use of nanozymes, as artificial enzyme mimics, may be a promising strategy to induce fungal death due to their advantages such as tunable catalytic activity, high stability, low cost, and easy preparation. Here, the importance of natural enzymes in the defense against fungi is outlined. The progress in antifungal performance and potential application of nanozymes and the related antifungal mechanisms are also summarized. Finally, the perspective and challenges in this field for future study, pointing out that nanozyme-based catalytic therapy represents a promising alternative strategy for antifungal treatment, are highlighted.

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Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

Medicinal Chemistry ◽

10.2174/1573406415666181203115957 ◽

2019 ◽

Vol 15 (6) ◽

pp. 648-658 ◽

Cited By ~ 1

Author(s):

Manzoor Ahmad Malik ◽

Shabir Ahmad Lone ◽

Parveez Gull ◽

Ovas Ahmad Dar ◽

Mohmmad Younus Wani ◽

...

Keyword(s):

Schiff Base ◽

Candida Albicans ◽

Antifungal Activity ◽

Fungal Infections ◽

Total Sterol ◽

Antifungal Drugs ◽

New Drugs ◽

Ergosterol Biosynthesis ◽

Dependent Manner ◽

Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

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Herbal Products and Their Active Constituents Used Alone and in Combination with Antifungal Drugs against Drug-Resistant Candida sp.

Antibiotics ◽

10.3390/antibiotics10060655 ◽

2021 ◽

Vol 10 (6) ◽

pp. 655

Author(s):

Anna Herman ◽

Andrzej Przemysław Herman

Keyword(s):

Biofilm Formation ◽

Fungal Infections ◽

Antifungal Drugs ◽

Membrane Transporters ◽

Drug Resistant ◽

Herbal Products ◽

Active Constituents ◽

Over Expression ◽

Candida Sp ◽

Current State

Clinical isolates of Candida yeast are the most common cause of opportunistic fungal infections resistant to certain antifungal drugs. Therefore, it is necessary to detect more effective antifungal agents that would be successful in overcoming such infections. Among them are some herbal products and their active constituents.The purpose of this review is to summarize the current state of knowledge onherbal products and their active constituents havingantifungal activity against drug-resistant Candida sp. used alone and in combination with antifungal drugs.The possible mechanisms of their action on drug-resistant Candida sp. including (1) inhibition of budding yeast transformation into hyphae; (2) inhibition of biofilm formation; (3) inhibition of cell wall or cytoplasmic membrane biosynthesis; (4) ROS production; and (5) over-expression of membrane transporters will be also described.

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GROWTH INHIBITORY ACTIVITIES OF THE RHIZOME CRUDE EXTRACT OF Curcuma longa ON THE HUMAN PATHOGENIC FUNGUS Mucor circinelloides

10.18173/2354-1059.2020-0051 ◽

2020 ◽

Vol 65 (10) ◽

pp. 82-91

Author(s):

Phuong Nguyen Anh ◽

Mai Le Thi Tuyet ◽

Trung Trieu Anh

Keyword(s):

Antifungal Activity ◽

Crude Extract ◽

Fungal Infections ◽

Early Stage ◽

Curcuma Longa ◽

Pathogenic Fungus ◽

Mucor Circinelloides ◽

Antifungal Drugs ◽

Diffusion Method ◽

Dilution Method

Mucormycosis is an uncommon but life-threatening invasive fungal infection, mostly occurs in immunocompromised patients. Lacking the appropriate antifungal drugs is one of the reasons that lead to difficulties in the management of mucormycosis. Curcuma longa has been used traditionally and widely to treat various diseases, including fungal infections. In the search for novel antifungal compounds from natural resources, we evaluated the effect of rhizome crude extract of C. longa on Mucor circinelloides – a causal agent of mucormycosis. The results of screening, using broth dilution method and agar-well diffusion method, showed that the C. longa extract exhibited promising antifungal activity against the fungus M. circinelloides. In liquid medium, C. longa extract decreased the ability of spore germination and the speed of hyphae formation of M. circinelloides decreased by up to approximately 70% and 90%, respectively. Besides, in a solid medium, the crude extract presented similar activity with amphotericin B (400 μg\mL) in decreasing the growth of M. circinelloides by nearly 77%. Moreover, the extract of C. longa also likely to induce the yeast-like type of growth of the dimorphic M. circinelloides in the early stage. These results suggest the plant could be a potential source for further study on biochemical components and the mechanism of its antifungal activity.

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