scholarly journals An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans

PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3000957
Author(s):  
Zeinab Mamouei ◽  
Shakti Singh ◽  
Bernard Lemire ◽  
Yiyou Gu ◽  
Abdullah Alqarihi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Mitochondrial Protein ◽  
Carbon Sources ◽  
Three Dimensional ◽  
Antifungal Drugs ◽  
Biofilm Growth ◽  
Biochemical Assays ◽  
Transport Chain ◽  
Biofilm Detachment

A forward genetic screening approach identified orf19.2500 as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by 3 evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I (CI) of the respiratory electron transport chain (ETC) and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary “gain” of new amino acid inserts that are also the functional hub of the protein.

scholarly journals An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans

2020 ◽  
Author(s):  
Zeinab Mamouei ◽  
Shakti Singh ◽  
Bernard Lemire ◽  
Yiyou Gu ◽  
Abdullah Alqarihi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Mitochondrial Protein ◽  
Carbon Sources ◽  
Three Dimensional ◽  
Antifungal Drugs ◽  
Biofilm Growth ◽  
Biochemical Assays ◽  
Transport Chain ◽  
Biofilm Detachment

AbstractA forward genetic screening approach identified orf19.2500, as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3-D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by three evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I of the respiratory electron transport chain, and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary “gain” of new amino acid inserts that are also the functional hub of the protein.

Octyl gallate triggers dysfunctional mitochondria leading to ROS driven membrane damage and metabolic inflexibility along with attenuated virulence in Candida albicans

2019 ◽  
Vol 58 (3) ◽  
pp. 380-392 ◽  
Author(s):  
Venkata Saibabu ◽  
Zeeshan Fatima ◽  
Kamal Ahmad ◽  
Luqman Ahmad Khan ◽  
Saif Hameed
Keyword(s):  
Candida Albicans ◽  
Isocitrate Lyase ◽  
Membrane Damage ◽  
Carbon Sources ◽  
Antifungal Drugs ◽  
In Vivo Studies ◽  
Haemolytic Activity ◽  
Metabolic Inflexibility ◽  
Underlying Mechanisms

Abstract Recently the high incidence of worldwide Candida infections has substantially increased. The growing problem about toxicity of antifungal drugs and multidrug resistance aggravates the need for the development of new effective strategies. Natural compounds in this context represent promising alternatives having potential to be exploited for improving human health. The present study was therefore designed to evaluate the antifungal effect of a naturally occurring phenolic, octyl gallate (OG), on Candida albicans and to investigate the underlying mechanisms involved. We demonstrated that OG at 25 μg/ml could effectively inhibit C. albicans. Mechanistic insights revealed that OG affects mitochondrial functioning as Candida cells exposed to OG did not grow on non-fermentable carbon sources. Dysfunctional mitochondria triggered generation of reactive oxygen species (ROS), which led to membrane damage mediated by lipid peroxidation. We explored that OG inhibited glucose-induced reduction in external pH and causes decrement in ergosterol levels by 45%. Furthermore, OG impedes the metabolic flexibility of C. albicans by inhibiting the glyoxylate enzyme isocitrate lyase, which was also confirmed by docking analysis. Additionally, OG affected virulence traits such as morphological transition and cell adherence. Furthermore, we depicted that OG not only prevented biofilm formation but eliminates the preformed biofilms. In vivo studies with Caenorhabditis elegans nematode model confirmed that OG could enhance the survival of C. elegans after infection with Candida. Toxicity assay using red blood cells showed only 27.5% haemolytic activity. Taken together, OG is a potent inhibitor of C. albicans that warrants further structural optimization and pharmacological investigations.

Biofilm formation by a biotechnologically important tropical marine yeast isolate, Yarrowia lipolytica NCIM 3589

2008 ◽  
Vol 58 (6) ◽  
pp. 1221-1229 ◽  
Author(s):  
D. H. Dusane ◽  
Y. V. Nancharaiah ◽  
V. P. Venugopalan ◽  
A. R. Kumar ◽  
S. S. Zinjarde
Keyword(s):  
Yarrowia Lipolytica ◽  
Biofilm Formation ◽  
Edible Oils ◽  
Carbon Sources ◽  
Three Dimensional ◽  
Ecological Niches ◽  
Lag Phase ◽  
Biofilm Growth ◽  
Water Media ◽  
Biofilm Development

Biofilm formation by Yarrowia lipolytica, a biotechnologically important fungus in microtitre plates, on glass slide surfaces and in flow cell was investigated. In microtitre plates, there was a short lag phase of adhesion followed by a period of rapid biofilm growth. The fungus formed extensive biofilms on glass slides, whereas in flow-cells a multicellular, three-dimensional microcolony structure was observed. The isolate formed biofilms in seawater and in fresh water media at neutral pH when grown in microtitre plates. The carbon sources differentially affected formation of biofilms in microtitre plates. Lactic acid, erythritol, glycerol, glucose and edible oils supported the formation of biofilms, while alkanes resulted in sub-optimal biofilm development. A variation in the morphology of the fungus was observed with different carbon sources. The results point to the possible existence of highly structured biofilms in varied ecological niches from where the yeast is isolated.

scholarly journals Combining Genome-Wide Gene Expression Analysis (RNA-seq) and a Gene Editing Platform (CRISPR-Cas9) to Uncover the Selectively Pro-oxidant Activity of Aurone Compounds Against Candida albicans

2021 ◽  
Vol 12 ◽  
Author(s):  
Fatmah M. Alqahtani ◽  
Scott T. Handy ◽  
Caleb L. Sutton ◽  
Mary B. Farone
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Functional Groups ◽  
Molecular Mechanisms ◽  
Ion Homeostasis ◽  
Bloodstream Infections ◽  
Antifungal Drugs ◽  
Transcriptional Analysis ◽  
Sulfur Amino Acid ◽  
Genome Wide

Candida albicans is the major fungal cause of healthcare-associated bloodstream infections worldwide with a 40% mortality rate. The scarcity of antifungal treatments due to the eukaryotic origin of fungal cells has challenged the development of selectively antifungal drugs. In an attempt to identify novel antifungal agents, aurones SH1009 and SH9051, as synthetically bioactive compounds, have been recently documented as anti-Candida agents. Since the molecular mechanisms behind the inhibitory activities of these aurones in C. albicans are unclear, this study aimed to determine the comprehensive cellular processes affected by these aurones and their molecular targets. Genome-wide transcriptional analysis of SH1009- and SH9051-treated C. albicans revealed uniquely repressed expression in different metabolic pathways, particularly trehalose and sulfur amino acid metabolic processes for SH1009 and SH9051, respectively. In contrast, the most commonly enriched process for both aurones was the up-regulation of RNA processing and ribosomal cleavages as an indicator of high oxidative stress, suggesting that a common aspect in the chemical structure of both aurones led to pro-oxidative properties. Additionally, uniquely induced responses (iron ion homeostasis for SH1009 and arginine biosynthesis for SH9051) garnered attention on key roles for the aurone functional groups. Deletion of the transcription factor for the trehalose biosynthesis pathway, Tye7p, resulted in an SH1009-resistant mutant, which also exhibited low trehalose content, validating the primary molecular target of SH1009. Aurone SH9051 uniquely simulated an exogenous supply of methionine or cysteine, leading to sulfur amino acid catabolism as evidenced by quantifying an overproduction of sulfite. Phenyl aurone, the common structure of aurones, contributed proportionally in the pro-oxidative activity through ferric ion reduction effects leading to high ROS levels. Our results determined selective and novel molecular mechanisms for aurone SH1009 and also elucidated the diverse cellular effects of different aurones based on functional groups.

scholarly journals Abstracts of an international conference “Biofilms II: Attachment and detachment in pure and mixed cultures”, held at the Leipziger Kubus UFZ Centre for Environmental Research, Leipzig, Germany, from 23 March to 24 March 2006

Biofilms ◽  
2005 ◽  
Vol 2 (4) ◽  
pp. 245-273
Keyword(s):  
Escherichia Coli ◽  
Biofilm Formation ◽  
Extracellular Polymeric Substances ◽  
Three Dimensional ◽  
Conjugative Plasmid ◽  
Environmental Research ◽  
Biofilm Growth ◽  
Biofilm Detachment ◽  
Biofilm Development

The effect of growth and detachment on formation of large-scale biofilm structureBiofilm cohesive energy density determination using a novel atomic force microscopy methodologyFluorescence correlation spectroscopy under two-photon excitation for the study of diffusion and reactivity of bacteriophage inside bacterial biofilmsBiothermodynamic characterization and dynamic analysis of biofilms using calorimetryBiomimetic antifouling coatings for sensor surfaces for water monitoring: performance control in defined biofilm cultures and under real environmental conditionsThe contribution of rpos to formation of Escherichia coli biofilmsSynergistic effects in mixed Escherichia coli biofilms: conjugative plasmid transfer drives biofilm expansionThe universal stress protein PA3309 in Pseudomonas aeruginosa is induced in biofilmsExtracellular polymeric substances from biofilms on membranes in waste-water treatment plantsBiofilm-to-planktonic cell yield: a strategy for proliferationPhysiological and phylogenetic characterization of the dispersed and loosely attached fraction of activated sludge flocsTowards a deterministic model of biofilm detachment: an experimental studyEffect of backwash on the characteristics of biofilm in a biological activated filter reactor using elemental sulfur particlesProcess performance and biomass properties in membrane-aerated bioreactorsBioaugmentation via conjugation in biofilms treating 3-chloroaniline: effects of selective pressureEffect of phosphorus on biofilm growth in a completely mixed biofilm reactorImpacts of biofilm development on reactive transport in porous media under variable flow regimensInfluence of biofilms on colloid mobility in the subsurfaceBiofilms in amendable in situ microcosms indicate relevant electron acceptor processes at a BTEX-contaminated aquiferFunctional biodiversity of complex biofilms grown on polychlorinated biphenyl oilIdentification and characterization of biofilm formation phenotypes of several clinically relevant Streptococcus pyogenes serotype strainsSelected probiotic bacteria disrupt biofilm development of vancomycin-resistant Enterococcus faeciumComparison of the extracellular polymeric substances of Candida albicans and Candida dubliniensis biofilmsInfluence of quorum-sensing regulated production of an antimicrobial component by Serratia plymuthica on establishment of dual species biofilms with Escherichia coliBiofilm formation by the thermophilic and cellulolytic actinomycete Thermobifida fuscaBiomonitoring of bacterial contamination on different surfaces of food-processing machinesRole of the flagella during the adhesion of Listeria monocytogenes EGD-e to inert surfaces after cultivation at different pHs and temperaturesAdhesion of Saccharomyces cerevisiae to stainless steel: influence of surface propertiesInvestigating the mechanical strength of biofilms with fluid dynamic gaugingThree-dimensional biofilm model with individual cells and continuum extracellular polymeric substances matrixA three-dimensional computer model analysis of four hypothetical biofilm detachment mechanismsModelling biofilm growth, detachment and fluid flow in a cross-section of tube reactorsBiofilm games

scholarly journals The Contribution of Candida albicans Vacuolar ATPase Subunit V1B, Encoded byVMA2, to Stress Response, Autophagy, and Virulence Is Independent of Environmental pH

2014 ◽  
Vol 13 (9) ◽  
pp. 1207-1221 ◽  
Author(s):  
Hallie S. Rane ◽  
Stella M. Bernardo ◽  
Summer R. Hayek ◽  
Jessica L. Binder ◽  
Karlett J. Parra ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Specific Activity ◽  
Carbon Sources ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Atpase Subunit ◽  
Content Type ◽  
Degradative Enzymes ◽  
And Function

ABSTRACTCandida albicansvacuoles are central to many critical biological processes, including filamentation andin vivovirulence. The V-ATPase proton pump is a multisubunit complex responsible for organellar acidification and is essential for vacuolar biogenesis and function. To study the function of the V1B subunit ofC. albicansV-ATPase, we constructed a tetracycline-regulatableVMA2mutant, tetR-VMA2. Inhibition ofVMA2expression resulted in the inability to grow at alkaline pH and altered resistance to calcium, cold temperature, antifungal drugs, and growth on nonfermentable carbon sources. Furthermore, V-ATPase was unable to fully assemble at the vacuolar membrane and was impaired in proton transport and ATPase-specific activity.VMA2repression led to vacuolar alkalinization in addition to abnormal vacuolar morphology and biogenesis. Key virulence-related traits, including filamentation and secretion of degradative enzymes, were markedly inhibited. These results are consistent with previous studies ofC. albicansV-ATPase; however, differential contributions of the V-ATPase Voand V1subunits to filamentation and secretion are observed. We also make the novel observation that inhibition ofC. albicansV-ATPase results in increased susceptibility to osmotic stress. Notably, V-ATPase inhibition under conditions of nitrogen starvation results in defects in autophagy. Lastly, we show the first evidence that V-ATPase contributes to virulence in an acidicin vivosystem by demonstrating that the tetR-VMA2mutant is avirulent in aCaenorhabditis elegansinfection model. This study illustrates the fundamental requirement of V-ATPase for numerous key virulence-related traits inC. albicansand demonstrates that the contribution of V-ATPase to virulence is independent of host pH.

scholarly journals Candida albicans Biofilms: a Developmental State Associated With Specific and Stable Gene Expression Patterns

2004 ◽  
Vol 3 (2) ◽  
pp. 536-545 ◽  
Author(s):  
Susana García-Sánchez ◽  
Sylvie Aubert ◽  
Ismaïl Iraqui ◽  
Guilhem Janbon ◽  
Jean-Marc Ghigo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Amino Acid ◽  
Expression Patterns ◽  
Developmental State ◽  
Amino Acid Biosynthesis ◽  
Antifungal Drugs ◽  
Stable Gene ◽  
Acid Biosynthesis ◽  
Mycelial Development

ABSTRACT Like many bacteria, yeast species can form biofilms on several surfaces. Candida albicans colonizes the surfaces of catheters, prostheses, and epithelia, forming biofilms that are extremely resistant to antifungal drugs. We have used transcript profiling to investigate the specific properties of C. albicans biofilms. Biofilm and planktonic cultures produced under different conditions of nutrient flow, aerobiosis, or glucose concentration were compared by overall gene expression correlation. Correlation was much higher between biofilms than planktonic populations irrespective of the growth conditions, indicating that biofilm populations formed in different environments display very similar and specific transcript profiles. A first cluster of 325 differentially expressed genes was identified. In agreement with the overrepresentation of amino acid biosynthesis genes in this cluster, Gcn4p, a regulator of amino acid metabolism, was shown to be required for normal biofilm growth. To identify biofilm-related genes that are independent of mycelial development, we studied the transcriptome of biofilms produced by a wild-type, hypha-producing strain and a cph1/cph1 efg1/efg1 strain defective for hypha production. This analysis identified a cluster of 317 genes expressed independently of hypha formation, whereas 86 genes were dependent on mycelial development. Both sets revealed the activation of the sulfur-amino acid biosynthesis pathway as a feature of C. albicans biofilms.

Biofilm formation by a biotechnologically important tropical marine yeast isolate, Yarrowia lipolytica NCIM 3589

2008 ◽  
Vol 58 (12) ◽  
pp. 2467-2475 ◽  
Author(s):  
D. H. Dusane ◽  
Y. V. Nancharaiah ◽  
V. P. Venugopalan ◽  
A. R. Kumar ◽  
S. S. Zinjarde
Keyword(s):  
Yarrowia Lipolytica ◽  
Biofilm Formation ◽  
Edible Oils ◽  
Carbon Sources ◽  
Three Dimensional ◽  
Ecological Niches ◽  
Lag Phase ◽  
Biofilm Growth ◽  
Water Media ◽  
Biofilm Development

Biofilm formation by Yarrowia lipolytica, a biotechnologically important fungus in microtitre plates, on glass slide surfaces and in flow cell was investigated. In microtitre plates, there was a short lag phase of adhesion followed by a period of rapid biofilm growth. The fungus formed extensive biofilms on glass slides, whereas in flow-cells a multicellular, three-dimensional microcolony structure was observed. The isolate formed biofilms in seawater and in fresh water media at neutral pH when grown in microtitre plates. The carbon sources differentially affected formation of biofilms in microtitre plates. Lactic acid, erythritol, glycerol, glucose and edible oils supported the formation of biofilms, while alkanes resulted in sub-optimal biofilm development. A variation in the morphology of the fungus was observed with different carbon sources. The results point to the possible existence of highly structured biofilms in varied ecological niches from where the yeast is isolated.

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

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
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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