Faculty Opinions recommendation of Computational and experimental approaches double the number of known introns in the pathogenic yeast Candida albicans.

Currently there is a gap between the rate of new antifungal development and the emergence of resistance among Candida clinical strains, particularly threatened by the extreme adhesiveness of C. albicans to indwelling medical devices. Two silver camphorimine complexes, [Ag(OH){OC10H14N(C6H4)2NC10H14O}] (compound P) and [{Ag(OC10H14NC6H4CH3-p)}2(μ-O)] (compound Q), are herein demonstrated as having high inhibiting activity towards the growth of Candida albicans and Candida glabrata clinical strains resistant to azoles, the frontline antifungals used in clinical practice. Compounds P and Q were also explored as bioactive coatings to prevent colonization by C. albicans and colonize the surface of indwelling medical devices, resulting in persistent infections. Functionalization of stainless steel with polycaprolactone (PCL) matrix embedded with compounds P or Q was reported for the first time to inhibit the colonization of C. albicans by 82% and 75%, respectively. The coating of PCL loaded with Q or P did not cause cytotoxic effects in mammalian cells, demonstrating the biocompatibility of the explored approach. The identification and further exploration of new approaches for surface engineering based on new molecules that can sensitize resistant strains, as herein demonstrated for complexes P and Q, is a significant step forward to improve the successful treatment of candidiasis.

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The Inflammatory Response Induced by Aspartic Proteases of Candida albicans Is Independent of Proteolytic Activity

Infection and Immunity ◽

10.1128/iai.00789-10 ◽

2010 ◽

Vol 78 (11) ◽

pp. 4754-4762 ◽

Cited By ~ 35

Author(s):

Donatella Pietrella ◽

Anna Rachini ◽

Neelam Pandey ◽

Lydia Schild ◽

Mihai Netea ◽

...

Keyword(s):

Candida Albicans ◽

Inflammatory Response ◽

Proteolytic Activity ◽

Necrosis Factor Alpha ◽

Pathogenic Yeast ◽

Aspartic Proteases ◽

Akt Activation ◽

Tnf Α ◽

Factor Alpha ◽

Pepstatin A

ABSTRACT The secretion of aspartic proteases (Saps) has long been recognized as a virulence-associated trait of the pathogenic yeast Candida albicans. In this study, we report that different recombinant Saps, including Sap1, Sap2, Sap3, and Sap6, have differing abilities to induce secretion of proinflammatory cytokines by human monocytes. In particular Sap1, Sap2, and Sap6 significantly induced interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 production. Sap3 was able to stimulate the secretion of IL-1β and TNF-α. All Saps tested were able to induce Ca2+ influx in monocytes. Treatment of these Saps with pepstatin A did not have any effect on cytokine secretion, indicating that their stimulatory potential was independent from their proteolytic activity. The capacity of Saps to induce inflammatory cytokine production was also independent from protease-activated receptor (PAR) activation and from the optimal pH for individual Sap activity. The interaction of Saps with monocytes induced Akt activation and phosphorylation of IκBα, which mediates translocation of NF-κB into the nucleus. Overall, these results suggest that individual Sap proteins can induce an inflammatory response and that this phenomenon is independent from the pH of a specific host niche and from Sap enzymatic activity. The inflammatory response is partially dependent on Sap denaturation and is triggered by the Akt/NF-κB activation pathway. Our data suggest a novel, activity-independent aspect of Saps during interactions of C. albicans with the host.

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Faculty Opinions recommendation of Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1164066.624734 ◽

2009 ◽

Author(s):

Joseph Heitman ◽

Ying-Lien Chen

Keyword(s):

Candida Albicans ◽

Pathogenic Yeast ◽

Echinocandin Resistance

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

mSphere ◽

10.1128/msphere.00913-19 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 2

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.

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Candida albicans sphingolipid C9-methyltransferase is involved in hyphal elongation

Microbiology ◽

10.1099/mic.0.033985-0 ◽

2010 ◽

Vol 156 (4) ◽

pp. 1234-1243 ◽

Cited By ~ 49

Author(s):

Takahiro Oura ◽

Susumu Kajiwara

Keyword(s):

Candida Albicans ◽

Lipid Membrane ◽

Hyphal Growth ◽

Pathogenic Fungi ◽

Wild Type ◽

Membrane Structures ◽

Pathogenic Yeast ◽

Chain Base ◽

Long Chain Base ◽

Long Chain

C9-methylated glucosylceramide is a fungus-specific sphingolipid. This lipid is a major membrane component in the cell and is thought to play important roles in the growth and virulence of several fungal species. To investigate the importance of the methyl branch of the long-chain base in glucosylceramides in pathogenic fungi, we identified and characterized a sphingolipid C9-methyltransferase gene (MTS1, C9-MethylTransferase for Sphingolipid 1) in the pathogenic yeast Candida albicans. The mts1 disruptant lacked (E,E)-9-methylsphinga-4,8-dienine in its glucosylceramides and contained (E)-sphing-4-enine and (E,E)-sphinga-4,8-dienine. Reintroducing the MTS1 gene into the mts1 disruptant restored the synthesis of (E,E)-9-methylsphinga-4,8-dienine in the glucosylceramides. We also created a disruptant of the HSX11 gene, encoding glucosylceramide synthase, which catalyses the final step of glucosylceramide synthesis, in C. albicans and compared this mutant with the mts1 disruptant. The C. albicans mts1 and hsx11 disruptants both had a decreased hyphal growth rate compared to the wild-type strain. The hsx11 disruptant showed increased susceptibility to SDS and fluconazole, similar to a previously reported sld1 disruptant that contained only (E)-sphing-4-enine in its glucosylceramides, suggesting that these strains have defects in their cell membrane structures. In contrast, the mts1 disruptant grew similarly to wild-type in medium containing SDS or fluconazole. These results suggest that the C9-methyl group of a long-chain base in glucosylceramides plays an important role in the hyphal elongation of C. albicans independent of lipid membrane disruption.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.4.763 ◽

1999 ◽

Vol 43 (4) ◽

pp. 763-768 ◽

Cited By ~ 52

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.

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Simple Carbohydrate Derivatives Diminish the Formation of Biofilm of the Pathogenic Yeast Candida albicans

Antibiotics ◽

10.3390/antibiotics9010010 ◽

2019 ◽

Vol 9 (1) ◽

pp. 10 ◽

Cited By ~ 1

Author(s):

Olena P. Ishchuk ◽

Olov Sterner ◽

Ulf Ellervik ◽

Sophie Manner

Keyword(s):

Candida Albicans ◽

Fungal Pathogen ◽

Biofilm Formation ◽

Untreated Control ◽

Morphological Transition ◽

Pathogenic Yeast ◽

Yeast Form ◽

Human Fungal Pathogen ◽

Morphological Transitions ◽

Simple Carbohydrate

The opportunistic human fungal pathogen Candida albicans relies on cell morphological transitions to develop biofilm and invade the host. In the current study, we developed new regulatory molecules, which inhibit the morphological transition of C. albicans from yeast-form cells to cells forming hyphae. These compounds, benzyl α-l-fucopyranoside and benzyl β-d-xylopyranoside, inhibit the hyphae formation and adhesion of C. albicans to a polystyrene surface, resulting in a reduced biofilm formation. The addition of cAMP to cells treated with α-l-fucopyranoside restored the yeast-hyphae switch and the biofilm level to that of the untreated control. In the β-d-xylopyranoside treated cells, the biofilm level was only partially restored by the addition of cAMP, and these cells remained mainly as yeast-form cells.

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