Revisiting the Vital Drivers and Mechanisms of β-Glucan Masking in Human Fungal Pathogen, Candida albicans

Among the several human fungal pathogens, Candida genus represents one of the most implicated in the clinical scenario. There exist several distinctive features that govern the establishment of Candida infections in addition to their capacity to adapt to multiple stress conditions inside humans which also include evasion of host immune responses. The complex fungal cell wall of the prevalent pathogen, Candida albicans, is one of the main targets of antifungal drugs and recognized by host immune cells. The wall consists of tiered arrangement of an outer thin but dense covering of mannan and inner buried layers of β-glucan and chitin. However, the pathogenic fungi adopt strategies to evade immune recognition by masking these molecules. This capacity to camouflage the immunogenic polysaccharide β-glucan from the host is a key virulence factor of C. albicans. The present review is an attempt to collate various underlying factors and mechanisms involved in Candida β-glucan masking from the available pool of knowledge and provide a comprehensive understanding. This will further improve therapeutic approaches to candidiasis by identifying new antifungal targets that blocks fungal immune evasion.

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Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

mSphere ◽

10.1128/msphere.00537-17 ◽

2018 ◽

Vol 3 (2) ◽

Cited By ~ 7

Author(s):

Eric H. Jung ◽

David J. Meyers ◽

Jürgen Bosch ◽

Arturo Casadevall

Keyword(s):

Candida Albicans ◽

Antifungal Activity ◽

Cryptococcus Neoformans ◽

Fungal Pathogens ◽

Pathogenic Fungi ◽

Cryptococcus Gattii ◽

Antifungal Drugs ◽

Resistant Bacteria ◽

Animal Cells ◽

Malaria Box

ABSTRACTSimilarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole againstCryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such asLomentospora prolificansandCryptococcus gattii. Antifungal activity was also observed against a common fungus,Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics.IMPORTANCEMuch like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity inPlasmodiumspp. for activity against two common fungal pathogens,Cryptococcus neoformansandCandida albicans, along with two less common pathogenic species,Lomentospora prolificansandCryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.

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Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen

10.1101/686881 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ognenka Avramovska ◽

Meleah A. Hickman

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Environmental Stress ◽

Genome Size ◽

Fungal Pathogen ◽

Fungal Pathogens ◽

Antifungal Drugs ◽

Relevant Model ◽

Human Fungal Pathogen ◽

Induced Mutagenesis

AbstractOrganismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploid C. albicans compared to diploid C. albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.

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Candida albicans: A Model Organism for Studying Fungal Pathogens

ISRN Microbiology ◽

10.5402/2012/538694 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 49

Author(s):

M. Anaul Kabir ◽

Mohammad Asif Hussain ◽

Zulfiqar Ahmad

Keyword(s):

Candida Albicans ◽

Fungal Pathogens ◽

Model Organism ◽

Antifungal Drugs ◽

Human Fungal Pathogen ◽

Disease Propagation ◽

Research Activities ◽

Close Relationship ◽

Pathogenic Microbes ◽

Host Parasite

Candida albicans is an opportunistic human fungal pathogen that causes candidiasis. As healthcare has been improved worldwide, the number of immunocompromised patients has been increased to a greater extent and they are highly susceptible to various pathogenic microbes and C. albicans has been prominent among the fungal pathogens. The complete genome sequence of this pathogen is now available and has been extremely useful for the identification of repertoire of genes present in this pathogen. The major challenge is now to assign the functions to these genes of which 13% are specific to C. albicans. Due to its close relationship with yeast Saccharomyces cerevisiae, an edge over other fungal pathogens because most of the technologies can be directly transferred to C. albicans from S. cerevisiae and it is amenable to mutation, gene disruption, and transformation. The last two decades have witnessed enormous amount of research activities on this pathogen that leads to the understanding of host-parasite interaction, infections, and disease propagation. Clearly, C. albicans has emerged as a model organism for studying fungal pathogens along with other two fungi Aspergillus fumigatus and Cryptococcus neoformans. Understanding its complete life style of C. albicans will undoubtedly be useful for developing potential antifungal drugs and tackling Candida infections. This will also shed light on the functioning of other fungal pathogens.

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Control of β-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence

PLoS Pathogens ◽

10.1371/journal.ppat.1010192 ◽

2022 ◽

Vol 18 (1) ◽

pp. e1010192

Author(s):

Mengli Yang ◽

Norma V. Solis ◽

Michaela Marshall ◽

Rachel Garleb ◽

Tingting Zhou ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Opportunistic Pathogen ◽

Antifungal Drugs ◽

Yeast Cells ◽

Immune Recognition ◽

Dependent Manner ◽

Wild Type ◽

Fungal Cell ◽

Disseminated Candidiasis

Candida albicans is a major opportunistic pathogen of humans. It can grow as morphologically distinct yeast, pseudohyphae and hyphae, and the ability to switch reversibly among different forms is critical for its virulence. The relationship between morphogenesis and innate immune recognition is not quite clear. Dectin-1 is a major C-type lectin receptor that recognizes β-glucan in the fungal cell wall. C. albicans β-glucan is usually masked by the outer mannan layer of the cell wall. Whether and how β-glucan masking is differentially regulated during hyphal morphogenesis is not fully understood. Here we show that the endo-1,3-glucanase Eng1 is differentially expressed in yeast, and together with Yeast Wall Protein 1 (Ywp1), regulates β-glucan exposure and Dectin-1-dependent immune activation of macrophage by yeast cells. ENG1 deletion results in enhanced Dectin-1 binding at the septa of yeast cells; while eng1 ywp1 yeast cells show strong overall Dectin-1 binding similar to hyphae of wild-type and eng1 mutants. Correlatively, hyphae of wild-type and eng1 induced similar levels of cytokines in macrophage. ENG1 expression and Eng1-mediated β-glucan trimming are also regulated by antifungal drugs, lactate and N-acetylglucosamine. Deletion of ENG1 modulates virulence in the mouse model of hematogenously disseminated candidiasis in a Dectin-1-dependent manner. The eng1 mutant exhibited attenuated lethality in male mice, but enhanced lethality in female mice, which was associated with a stronger renal immune response and lower fungal burden. Thus, Eng1-regulated β-glucan exposure in yeast cells modulates the balance between immune protection and immunopathogenesis during disseminated candidiasis.

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Harnessing Metal Homeostasis Offers Novel and Promising Targets Against Candida albicans

Current Drug Discovery Technologies ◽

10.2174/1570163816666190227231437 ◽

2020 ◽

Vol 17 (4) ◽

pp. 415-429

Author(s):

Saif Hameed ◽

Sandeep Hans ◽

Shweta Singh ◽

Zeeshan Fatima

Keyword(s):

Candida Albicans ◽

Fungal Infections ◽

Critical Factor ◽

Pathogenic Fungi ◽

Multidrug Resistant ◽

Antifungal Drugs ◽

Human Fungal Pathogen ◽

Nutritional Immunity ◽

Metabolic Functions ◽

Candida Infections

Fungal infections, particularly of Candida species, which are the commensal organisms of human, are one of the major debilitating diseases in immunocompromised patients. The limited number of antifungal drugs available to treat Candida infections, with the concomitant increasing incidence of multidrug-resistant (MDR) strains, further worsens the therapeutic options. Thus, there is an urgent need for the better understanding of MDR mechanisms, and their reversal, by employing new strategies to increase the efficacy and safety profiles of currently used therapies against the most prevalent human fungal pathogen, Candida albicans. Micronutrient availability during C. albicans infection is regarded as a critical factor that influences the progression and magnitude of the disease. Intracellular pathogens colonize a variety of anatomical locations that are likely to be scarce in micronutrients, as a defense strategy adopted by the host, known as nutritional immunity. Indispensable critical micronutrients are required both by the host and by C. albicans, especially as a cofactor in important metabolic functions. Since these micronutrients are not freely available, C. albicans need to exploit host reservoirs to adapt within the host for survival. The ability of pathogenic organisms, including C. albicans, to sense and adapt to limited micronutrients in the hostile environment is essential for survival and confers the basis of its success as a pathogen. This review describes that micronutrients availability to C. albicans is a key attribute that may be exploited when one considers designing strategies aimed at disrupting MDR in this pathogenic fungi. Here, we discuss recent advances that have been made in our understanding of fungal micronutrient acquisition and explore the probable pathways that may be utilized as targets.

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Biosynthesis of selenium nanoparticles by Aspergillus flavus and Candida albicans and comparison of their effects with antifungal drugs

10.21203/rs.3.rs-194546/v1 ◽

2021 ◽

Author(s):

Mahdi Hosseini Bafghi ◽

Razieh Nazari ◽

Majid Darroudi ◽

Mohsen Zargar ◽

Hossein Zarrinfar

Keyword(s):

Candida Albicans ◽

Aspergillus Flavus ◽

Fungal Pathogens ◽

Chemical Properties ◽

Cost Effective ◽

Antifungal Drugs ◽

Selenium Nanoparticles ◽

Fungal Strains ◽

Vis Spectroscopy ◽

Physical And Chemical

Abstract Biosynthesis of nanoparticles can stand as a replacement for the available chemical and physical methods by offering new procedures as green syntheses that have proved to be simple, biocompatible, safe, and cost-effective. Considering how nanoparticles with a size of 1 to 100 nanometers contain unique physical and chemical properties, recent reports are indicative of observing the antifungal qualities of selenium nanoparticles (Se-NPs). Recently, the observance of antifungal resistance towards different species of these fungi is often reported. Therefore, due to the antifungal effects of biological nanoparticles, this study aimed to investigate the exertion of these nanoparticles and evaluate their effects on the growth of fungal pathogens. Se-NPs were biosynthesized by the application of wet reduction method, which included specific concentrations of Aspergillus flavus and Candida albicans. The presence of nanoparticles was confirmed by methods such as UV-Vis spectroscopy, FT-IR analysis, and FESEM electron microscope that involved FESEM and EDAX diagram. The fungal strains were cultured in sabouraud dextrose agar medium to perform the sensitivity test based on the minimum inhibitory concentration (MIC) method in duplicate. The utilization of Se-NPs at concentrations of 1 µg/ ml and below resulted in zero growth of fungal agents. However, their growth was inhibited by antifungal drugs at concentrations of 2 µg/ ml and higher. Based on the obtained results, biological nanoparticles produced by fungal agents at different concentrations exhibited favorable inhibitory effects on the growth of fungal strains.

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In Fungal Intracellular Pathogenesis, Form Determines Fate

mBio ◽

10.1128/mbio.02092-18 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 4

Author(s):

Robin C. May ◽

Arturo Casadevall

Keyword(s):

Candida Albicans ◽

Fungal Pathogen ◽

Membrane Integrity ◽

Pathogenic Fungi ◽

Morphological Transition ◽

Physical Damage ◽

Fungal Cell ◽

Morphological Transitions ◽

Pathogenic Microbes ◽

Phagosomal Membrane

ABSTRACT For pathogenic microbes to survive ingestion by macrophages, they must subvert powerful microbicidal mechanisms within the phagolysosome. After ingestion, Candida albicans undergoes a morphological transition producing hyphae, while the surrounding phagosome exhibits a loss of phagosomal acidity. However, how these two events are related has remained enigmatic. Now Westman et al. (mBio 9:e01226-18, 2018, https://doi.org/10.1128/mBio.01226-18) report that phagosomal neutralization results from disruption of phagosomal membrane integrity by the enlarging hyphae, directly implicating the morphological transition in physical damage that promotes intracellular survival. The C. albicans intracellular strategy shows parallels with another fungal pathogen, Cryptococcus neoformans, where a morphological changed involving capsular enlargement intracellularly is associated with loss of membrane integrity and death of the host cell. These similarities among distantly related pathogenic fungi suggest that morphological transitions that are common in fungi directly affect the outcome of the fungal cell-macrophage interaction. For this class of organisms, form determines fate in the intracellular environment.

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Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00214-15 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3460-3468 ◽

Cited By ~ 7

Author(s):

Rui Li ◽

Sumant Puri ◽

Swetha Tati ◽

Paul J. Cullen ◽

Mira Edgerton

Keyword(s):

Candida Albicans ◽

Protein Kinase ◽

Antifungal Drugs ◽

Mitogen Activated Protein Kinase ◽

Fungal Cell ◽

Content Type ◽

Histatin 5 ◽

Mitogen Activated Protein ◽

Hyphal Formation ◽

Sensor Proteins

ABSTRACTCandida albicansis a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC.C. albicanssenses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either byN-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility ofC. albicanscells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility inC. albicans.

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Chaperone Networks in Fungal Pathogens of Humans

Journal of Fungi ◽

10.3390/jof7030209 ◽

2021 ◽

Vol 7 (3) ◽

pp. 209

Author(s):

Linda C. Horianopoulos ◽

James W. Kronstad

Keyword(s):

Immune Response ◽

Candida Albicans ◽

Fungal Pathogens ◽

Morphological Changes ◽

Antifungal Drugs ◽

Promising Strategy ◽

Human Body Temperature ◽

Small Hsps ◽

J Domain ◽

Shock Proteins

The heat shock proteins (HSPs) function as chaperones to facilitate proper folding and modification of proteins and are of particular importance when organisms are subjected to unfavourable conditions. The human fungal pathogens are subjected to such conditions within the context of infection as they are exposed to human body temperature as well as the host immune response. Herein, the roles of the major classes of HSPs are briefly reviewed and their known contributions in human fungal pathogens are described with a focus on Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. The Hsp90s and Hsp70s in human fungal pathogens broadly contribute to thermotolerance, morphological changes required for virulence, and tolerance to antifungal drugs. There are also examples of J domain co-chaperones and small HSPs influencing the elaboration of virulence factors in human fungal pathogens. However, there are diverse members in these groups of chaperones and there is still much to be uncovered about their contributions to pathogenesis. These HSPs do not act in isolation, but rather they form a network with one another. Interactions between chaperones define their specific roles and enhance their protein folding capabilities. Recent efforts to characterize these HSP networks in human fungal pathogens have revealed that there are unique interactions relevant to these pathogens, particularly under stress conditions. The chaperone networks in the fungal pathogens are also emerging as key coordinators of pathogenesis and antifungal drug tolerance, suggesting that their disruption is a promising strategy for the development of antifungal therapy.

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Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids

mBio ◽

10.1128/mbio.00647-15 ◽

2015 ◽

Vol 6 (3) ◽

Cited By ~ 64

Author(s):

Visesato Mor ◽

Antonella Rella ◽

Amir M. Farnoud ◽

Ashutosh Singh ◽

Mansa Munshi ◽

...

Keyword(s):

Cell Cycle Progression ◽

Fungal Infections ◽

Pathogenic Fungi ◽

Antifungal Drugs ◽

Sequencing Analysis ◽

Fungal Cell ◽

New Class ◽

Narrow Spectrum

ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.

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