scholarly journals Modulation of Morphogenesis in Candida albicans by Various Small Molecules

2011 ◽  
Vol 10 (8) ◽  
pp. 1004-1012 ◽  
Author(s):  
Julie Shareck ◽  
Pierre Belhumeur
Keyword(s):  
Candida Albicans ◽  
Small Molecules ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Antifungal Drugs ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Life Threatening ◽  
Experimental Findings ◽  
Cell Cycle Inhibitors

ABSTRACTThe pathogenic yeastCandida albicans, a member of the mucosal microbiota, is responsible for a large spectrum of infections, ranging from benign thrush and vulvovaginitis in both healthy and immunocompromised individuals to severe, life-threatening infections in immunocompromised patients. A striking feature ofC. albicansis its ability to grow as budding yeast and as filamentous forms, including hyphae and pseudohyphae. The yeast-to-hypha transition contributes to the overall virulence ofC. albicansand may even constitute a target for the development of antifungal drugs. Indeed, impairing morphogenesis inC. albicanshas been shown to be a means to treat candidiasis. Additionally, a large number of small molecules such as farnesol, fatty acids, rapamycin, geldanamycin, histone deacetylase inhibitors, and cell cycle inhibitors have been reported to modulate the yeast-to-hypha transition inC. albicans. In this minireview, we take a look at molecules that modulate morphogenesis in this pathogenic yeast. When possible, we address experimental findings regarding their mechanisms of action and their therapeutic potential. We discuss whether or not modulating morphogenesis constitutes a strategy to treatCandidainfections.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

scholarly journals Mucins Suppress Virulence Traits of Candida albicans

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Nicole L. Kavanaugh ◽  
Angela Q. Zhang ◽  
Clarissa J. Nobile ◽  
Alexander D. Johnson ◽  
Katharina Ribbeck
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Therapeutic Potential ◽  
Content Type ◽  
Environmental Signals ◽  
Healthy Humans ◽  
Normal Microbiota ◽  
Life Threatening ◽  
Main Components

ABSTRACTCandida albicansis the most prevalent fungal pathogen of humans, causing a variety of diseases ranging from superficial mucosal infections to deep-seated systemic invasions. Mucus, the gel that coats all wet epithelial surfaces, accommodatesC. albicansas part of the normal microbiota, whereC. albicansresides asymptomatically in healthy humans. Through a series ofin vitroexperiments combined with gene expression analysis, we show that mucin biopolymers, the main gel-forming constituents of mucus, induce a new oval-shaped morphology inC. albicansin which a range of genes related to adhesion, filamentation, and biofilm formation are downregulated. We also show that corresponding traits are suppressed, renderingC. albicansimpaired in forming biofilms on a range of different synthetic surfaces and human epithelial cells. Our data suggest that mucins can manipulateC. albicansphysiology, and we hypothesize that they are key environmental signals for retainingC. albicansin the host-compatible, commensal state.IMPORTANCEThe yeastCandida albicanscauses both superficial infections of the mucosa and life-threatening infections upon entering the bloodstream. However,C. albicansis not always harmful and can exist as part of the normal microbiota without causing disease. Internal body surfaces that are susceptible to infection byC. albicansare coated with mucus, which we hypothesize plays an important role in preventing infections. Here, we show that the main components of mucus, mucin glycoproteins, suppress virulence attributes ofC. albicansat the levels of gene expression and the corresponding morphological traits. Specifically, mucins suppress attachment to plastic surfaces and human cells, the transition to cell-penetrating hyphae, and the formation of biofilms (drug-resistant microbial communities). Additionally, exposure to mucins induces an elongated morphology that physically resembles the mating-competent opaque state but is phenotypically distinct. We suggest that mucins are potent antivirulence molecules that have therapeutic potential for suppressingC. albicansinfections.

scholarly journals Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in Candida albicans

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Qinxi Ma ◽  
Mihaela Ola ◽  
Elise Iracane ◽  
Geraldine Butler
Keyword(s):  
Fatty Acids ◽  
Candida Albicans ◽  
Chromosome Number ◽  
Antifungal Drugs ◽  
Chromosome 7 ◽  
Chromosome 2 ◽  
Adaptation To Stress ◽  
Pathogenic Yeast ◽  
Gene Deletions ◽  
Content Type

Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeastCandida albicansand are associated with adaptation to stress and to antifungal drugs. Aneuploidy and LOH can also be induced during laboratory manipulations, such as during genetic transformation. We find thatC. albicansstrain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. One deletion strain generated in this background has acquired extra copies of chromosomes 5 and 7. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids.

scholarly journals Metabolic Reprogramming in the Opportunistic Yeast Candida albicans in Response to Hypoxia

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Anaïs Burgain ◽  
Faiza Tebbji ◽  
Inès Khemiri ◽  
Adnane Sellam
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Metabolic Pathways ◽  
Membrane Lipids ◽  
Oxygen Depletion ◽  
Metabolic Reprogramming ◽  
Pathogenic Yeast ◽  
Fungal Virulence ◽  
Content Type ◽  
The Impact

ABSTRACT Hypoxia is the predominant condition that the human opportunistic fungus Candida albicans encounters in the majority of the colonized niches within the host. So far, the impact of such a condition on the overall metabolism of this important human-pathogenic yeast has not been investigated. Here, we have undertaken a time-resolved metabolomics analysis to uncover the metabolic landscape of fungal cells experiencing hypoxia. Our data showed a dynamic reprogramming of many fundamental metabolic pathways, such as glycolysis, the pentose phosphate pathway, and different metabolic routes related to fungal cell wall biogenesis. The C. albicans lipidome was highly affected by oxygen depletion, with an increased level of free fatty acids and biochemical intermediates of membrane lipids, including phospholipids, lysophospholipids, sphingolipids, and mevalonate. The depletion of oxygen-dependent lipids such as ergosterol or phosphatidylcholine with longer and polyunsaturated lateral fatty acid chains was observed only at the later hypoxic time point (180 min). Transcriptomics data supported the main metabolic response to hypoxia when matched to our metabolomic profiles. The hypoxic metabolome reflected different physiological alterations of the cell wall and plasma membrane of C. albicans under an oxygen-limiting environment that were confirmed by different approaches. This study provided a framework for future in vivo investigations to examine relevant hypoxic metabolic trajectories in fungal virulence and fitness within the host. IMPORTANCE A critical aspect of cell fitness is the ability to sense and adapt to variations in oxygen levels in their local environment. Candida albicans is an opportunistic yeast that is the most prevalent human fungal pathogen. While hypoxia is the predominant condition that C. albicans encounters in most of its niches, its impact on fungal metabolism remains unexplored so far. Here, we provided a detailed landscape of the C. albicans metabolome that emphasized the importance of many metabolic routes for the adaptation of this yeast to oxygen depletion. The fungal hypoxic metabolome identified in this work provides a framework for future investigations to assess the contribution of relevant metabolic pathways in the fitness of C. albicans and other human eukaryotic pathogens with similar colonized human niches. As hypoxia is present at most of the fungal infection foci in the host, hypoxic metabolic pathways are thus an attractive target for antifungal therapy.

scholarly journals Effects of Azole Antifungal Drugs on the Transition from Yeast Cells to Hyphae in Susceptible and Resistant Isolates of the Pathogenic Yeast Candida albicans

1999 ◽  
Vol 43 (4) ◽  
pp. 763-768 ◽  
Author(s):  
Kien C. Ha ◽  
Theodore C. White
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Pathogenic Yeast ◽  
Oral Infections ◽  
Antifungal Drug Resistance ◽  
Hyphal Formation

ABSTRACT Oral infections caused by the yeast Candida albicansare some of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug resistance, creating a major problem in the treatment of yeast infections in AIDS patients and other immunocompromised individuals. Several molecular mechanisms that contribute to drug resistance have been identified. InC. albicans, the ability to morphologically switch from yeast cells (blastospores) to filamentous forms (hyphae) is an important virulence factor which contributes to the dissemination ofCandida in host tissues and which promotes infection and invasion. A positive correlation between the level of antifungal drug resistance and the ability to form hyphae in the presence of azole drugs has been identified. Under hypha-inducing conditions in the presence of an azole drug, resistant clinical isolates form hyphae, while susceptible yeast isolates do not. This correlation is observed in a random sample from a population of susceptible and resistant isolates and is independent of the mechanisms of resistance.35S-methionine incorporation suggests that growth inhibition is not sufficient to explain the inhibition of hyphal formation, but it may contribute to this inhibition.

scholarly journals Functional Dissection of a Candida albicans Zinc Cluster Transcription Factor, the Multidrug Resistance Regulator Mrr1

2011 ◽  
Vol 10 (8) ◽  
pp. 1110-1121 ◽  
Author(s):  
Sabrina Schubert ◽  
Christina Popp ◽  
P. David Rogers ◽  
Joachim Morschhäuser
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Transcriptional Activation ◽  
Efflux Pump ◽  
Major Facilitator Superfamily ◽  
Constitutive Activity ◽  
Activation Domain ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Zinc Cluster

ABSTRACTThe overexpression of theMDR1gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the widely used antimycotic agent fluconazole and other toxic compounds in the pathogenic yeastCandida albicans. The zinc cluster transcription factor Mrr1 controlsMDR1expression in response to inducing chemicals, and gain-of-function mutations inMRR1are responsible for the constitutiveMDR1upregulation in fluconazole-resistantC. albicansstrains. To understand how Mrr1 activity is regulated, we identified functional domains of this transcription factor. A hybrid protein consisting of the N-terminal 106 amino acids of Mrr1 and the transcriptional activation domain of Gal4 fromSaccharomyces cerevisiaeconstitutively inducedMDR1expression, demonstrating that the DNA binding domain is sufficient to target Mrr1 to theMDR1promoter. Using a series of C-terminal truncations and systematic internal deletions, we could show that Mrr1 contains multiple activation and inhibitory domains. One activation domain (AD1) is located in the C terminus of Mrr1. When fused to the tetracycline repressor TetR, this distal activation domain induced gene expression from a TetR-dependent promoter. The deletion of an inhibitory region (ID1) located near the distal activation domain resulted in constitutive activity of Mrr1. The additional removal of AD1 abolished the constitutive activity, but the truncated Mrr1 still could activate theMDR1promoter in response to the inducer benomyl. These results demonstrate that the activity of Mrr1 is regulated in multiple ways and provide insights into the function of an important mediator of drug resistance inC. albicans.

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

2015 ◽  
Vol 59 (6) ◽  
pp. 3460-3468 ◽  
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.

scholarly journals The Evolutionary Rewiring of Ubiquitination Targets Has Reprogrammed the Regulation of Carbon Assimilation in the Pathogenic Yeast Candida albicans

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Doblin Sandai ◽  
Zhikang Yin ◽  
Laura Selway ◽  
David Stead ◽  
Janet Walker ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fatty Acids ◽  
Candida Albicans ◽  
Isocitrate Lyase ◽  
Carbon Sources ◽  
Carbon Assimilation ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Catabolite Inactivation ◽  
Accelerated Degradation

ABSTRACTMicrobes must assimilate carbon to grow and colonize their niches. Transcript profiling has suggested thatCandida albicans, a major pathogen of humans, regulates its carbon assimilation in an analogous fashion to the model yeastSaccharomyces cerevisiae, repressing metabolic pathways required for the use of alterative nonpreferred carbon sources when sugars are available. However, we show that there is significant dislocation between the proteome and transcriptome inC. albicans. Glucose triggers the degradation of theICL1andPCK1transcripts inC. albicans, yet isocitrate lyase (Icl1) and phosphoenolpyruvate carboxykinase (Pck1) are stable and are retained. Indeed, numerous enzymes required for the assimilation of carboxylic and fatty acids are not degraded in response to glucose. However, when expressed inC. albicans,S. cerevisiaeIcl1 (ScIcl1) is subjected to glucose-accelerated degradation, indicating that likeS. cerevisiae, this pathogen has the molecular apparatus required to execute ubiquitin-dependent catabolite inactivation.C. albicansIcl1 (CaIcl1) lacks analogous ubiquitination sites and is stable under these conditions, but the addition of a ubiquitination site programs glucose-accelerated degradation of CaIcl1. Also, catabolite inactivation is slowed inC. albicans ubi4cells. Ubiquitination sites are present in gluconeogenic and glyoxylate cycle enzymes fromS. cerevisiaebut absent from theirC. albicanshomologues. We conclude that evolutionary rewiring of ubiquitination targets has meant that following glucose exposure,C. albicansretains key metabolic functions, allowing it to continue to assimilate alternative carbon sources. This metabolic flexibility may be critical during infection, facilitating the rapid colonization of dynamic host niches containing complex arrays of nutrients.IMPORTANCEPathogenic microbes must assimilate a range of carbon sources to grow and colonize their hosts. Current views about carbon assimilation in the pathogenic yeastCandida albicansare strongly influenced by theSaccharomyces cerevisiaeparadigm in which cells faced with choices of nutrients first use energetically favorable sugars, degrading enzymes required for the assimilation of less favorable alternative carbon sources. We show that this is not the case inC. albicansbecause there has been significant evolutionary rewiring of the molecular signals that promote enzyme degradation in response to glucose. As a result, this major pathogen of humans retains enzymes required for the utilization of physiologically relevant carbon sources such as lactic acid and fatty acids, allowing it to continue to use these host nutrients even when glucose is available. This phenomenon probably enhances efficient colonization of host niches where sugars are only transiently available.

scholarly journals Conjugated Linoleic Acid Inhibits Hyphal Growth in Candida albicans by Modulating Ras1p Cellular Levels and Downregulating TEC1 Expression

2011 ◽  
Vol 10 (4) ◽  
pp. 565-577 ◽  
Author(s):  
Julie Shareck ◽  
André Nantel ◽  
Pierre Belhumeur
Keyword(s):  
Candida Albicans ◽  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Cellular Localization ◽  
Therapeutic Potential ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Cellular Growth ◽  
Content Type ◽  
Protein Levels

ABSTRACTThe polymorphic yeastCandida albicansexists in yeast and filamentous forms. Given that the morphogenetic switch coincides with the expression of many virulence factors, the yeast-to-hypha transition constitutes an attractive target for the development of new antifungal agents. Since an untapped therapeutic potential resides in small molecules that hinderC. albicansfilamentation, we characterized the inhibitory effect of conjugated linoleic acid (CLA) on hyphal growth and addressed its mechanism of action. CLA inhibited hyphal growth in a dose-dependent fashion in both liquid and solid hypha-inducing media. The fatty acid blocked germ tube formation without affecting cellular growth rates. Global transcriptional profiling revealed that CLA downregulated the expression of hypha-specific genes and abrogated the induction of several regulators of hyphal growth, includingTEC1,UME6,RFG1, andRAS1. However, neitherUME6norRFG1was necessary for CLA-mediated hyphal growth inhibition. Expression analysis showed that the downregulation ofTEC1expression levels by CLA depended onRAS1. In addition, whileRAS1transcript levels remained constant in CLA-treated cells, its protein levels declined with time. With the use of a strain expressing GFP-Ras1p, CLA treatment was also shown to affect Ras1p localization to the plasma membrane. These findings suggest that CLA inhibits hyphal growth by affecting the cellular localization of Ras1p and blocking the increase inRAS1mRNA and protein levels. Combined, these effects should prevent the induction of the Ras1p signaling pathway. This study provides the biological and molecular explanations that underlie CLA's ability to inhibit hyphal growth inC. albicans.

scholarly journals Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs

2015 ◽  
Vol 60 (3) ◽  
pp. 1646-1655 ◽  
Author(s):  
Chantal Fernandes ◽  
Rafael Prados-Rosales ◽  
Branca M. A. Silva ◽  
Antonio Nakouzi-Naranjo ◽  
Mónica Zuzarte ◽  
...  
Keyword(s):  
Cell Walls ◽  
Therapeutic Potential ◽  
Morphological Changes ◽  
Antifungal Drugs ◽  
Protective Mechanism ◽  
Melanin Synthesis ◽  
Melanin Production ◽  
Minimum Effective Concentration ◽  
Content Type ◽  
Alternaria Infectoria

The importance ofAlternariaspecies fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses onAlternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced byA. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate thatA. infectoriaincreased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate thatA. infectoriaactivates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organizedA. infectoriacell walls. In summary,A. infectoriasynthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.

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