scholarly journals Tolerance to fluconazole in Candida albicans is regulated by temperature and aneuploidy

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
FENG YANG ◽  
YUANYING JIANG ◽  
JUDITH BERMAN
Keyword(s):  
Candida Albicans ◽  
High Temperature ◽  
Fungal Pathogen ◽  
Drug Tolerance ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Human Fungal Pathogen ◽  
Genes Encoding ◽  
Aneuploid Chromosome ◽  
Definition Of

Candida albicans is a prevalent human fungal pathogen. Azoles are the most widely used antifungal drugs. Drug tolerance in bacteria is well defined and thoroughly studied, but in fungi, the definition of drug tolerance and the mechanism that drive it are not well understood. Here, we found that a large proportion of clinical isolates were intrinsically tolerant to fluconazole, and/or could be induced by high temperature (37°C) to become tolerant (conditionally tolerant). When treated with inhibitory doses of fluconazole, non-tolerant strains became tolerant by forming aneuploids involving different chromosomes, with chromosome R duplication as the most recurrent mechanism. Tolerance determines the ability to grow in the presence of fluconazole and other azoles, in a manner independent of the MIC. Both temperature conditional tolerance and the associated aneuploidy were sensitive to FK506, an inhibitor of calcineurin. Intrinsic and conditional tolerance were also abolished by deletions of genes encoding the calcineurin (CMP1 and CNB1). However, the dependence of tolerance on calcineurin could be bypassed by a different aneuploid chromosome. Thus, fluconazole tolerance in C. albicans is regulated by temperature and by aneuploidy and is dependent upon aneuploidy, but this dependence can be bypassed by an additional aneuploidy.

scholarly journals Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Jessica L. Chitty ◽  
Mark S. Butler ◽  
Azzah Suboh ◽  
David J. Edwards ◽  
Matthew A. Cooper ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Cyclic Lipopeptide ◽  
Structure Activity ◽  
Cryptococcus Species ◽  
Insight Into ◽  
Better Than

ABSTRACTResistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogenCryptococcus neoformansis a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 μg/ml. Further testing of octapeptin C4 against 40 clinical isolates ofC. neoformansvar.grubiiorneoformansshowed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates ofC. neoformansvar.gattiihad an MIC of 0.78 to 12.5 μg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule ofC. neoformansinfluences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents.

scholarly journals The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans

2021 ◽  
Author(s):  
Marzia Rizzo ◽  
Natthapon Soisangwan ◽  
Jan Soetaert ◽  
Samuel Vega-Estevez ◽  
Anna Selmecki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Genome Instability ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Genome Plasticity ◽  
Sumo Protease ◽  
Human Fungal Pathogen ◽  
Life Threatening

AbstractStress-induced genome instability in microbial organisms is emerging as a critical regulatory mechanism for driving rapid and reversible adaption to drastic environmental changes. In Candida albicans, a human fungal pathogen that causes life-threatening infections, genome plasticity confers increased virulence and antifungal drug resistance. Discovering the mechanisms regulating C. albicans genome plasticity is a priority to understand how this and other microbial pathogens establish life-threatening infections and develop resistance to antifungal drugs. We identified the SUMO protease Ulp2 as a critical regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to hypersensitivity to genotoxic agents and increased genome instability. This increased genome diversity causes reduced fitness under standard laboratory growth conditions but enhances adaptation to stress, making ulp2Δ/Δ cells more likely to thrive in the presence of antifungal drugs. Whole-genome sequencing indicates that ulp2Δ/Δ cells counteract antifungal drug-induced stress by developing segmental aneuploidies of chromosome R and chromosome I. We demonstrate that intrachromosomal repetitive elements drive the formation of complex novel genotypes with adaptive power.

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

2019 ◽  
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.

scholarly journals Chromosome 1 trisomy overcomes the block of sphingolipid biosynthesis caused by aureobasidin A and confers pleiotropic effects on susceptibility to antifungals in Candida albicans

2020 ◽  
Author(s):  
Yi Xu ◽  
Feng Yang
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Membrane Lipid ◽  
Antifungal Drugs ◽  
Pleiotropic Effects ◽  
Chromosome 1 ◽  
Eukaryotic Cells ◽  
Human Fungal Pathogen ◽  
Aureobasidin A ◽  
Sphingolipid Biosynthesis

AbstractSphingolipids are important membrane lipid components of eukaryotic cells. In Candida albicans, chromosome 1 trisomy not only overcame the block of sphingolipid biosynthesis caused by aureobasidin A, but also altered tolerance to three of the four major classes of antifungal drugs. Two haploinsufficient genes on chromosome 1, PDR16 and IPT1, were associated with tolerance to aureobasidin A. This study illustrates an example of multi-drug tolerance caused by aneuploidy in the human fungal pathogen C. albicans.

scholarly journals Antifungal effects of alantolactone on Candida albicans: an in vitro study

2021 ◽  
Author(s):  
Xin Liu ◽  
Lili Zhong ◽  
Zhiming Ma ◽  
Yujie Sui ◽  
Jia’nan Xie ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Medical Devices ◽  
Fungal Pathogen ◽  
Biofilm Formation ◽  
In Vitro Study ◽  
Antifungal Drugs ◽  
Promising Candidate ◽  
Human Fungal Pathogen ◽  
Antifungal Effects

AbstractThe human fungal pathogen Candida albicans can cause many kinds of infections, including biofilm infections on medical devices, while the available antifungal drugs are limited to only a few. In this study, alantolactone (Ala) demonstrated antifungal activities against C. albicans, as well as other Candida species, with a MIC of 72 μg/mL. Ala could also inhibit the adhesion, yeast-to-hyphal transition, biofilm formation and development of C. albicans. The exopolysaccharide of biofilm matrix and extracellular phospholipase production could also be reduced by Ala treatment. Ala could increase permeability of C. albicans cell membrane and ROS contribute to the antifungal activity of Ala. Overall, the present study suggests that Ala may provide a promising candidate for developing antifungal drugs against C. albicans infections.

scholarly journals Sur7 Promotes Plasma Membrane Organization and Is Needed for Resistance to Stressful Conditions and to the Invasive Growth and Virulence of Candida albicans

mBio ◽  
2011 ◽  
Vol 3 (1) ◽  
Author(s):  
Lois M. Douglas ◽  
Hong X. Wang ◽  
Sabine Keppler-Ross ◽  
Neta Dean ◽  
James B. Konopka
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Fungal Pathogen ◽  
Antifungal Drugs ◽  
Membrane Organization ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Membrane Compartment ◽  
Systemic Infections

ABSTRACTThe human fungal pathogenCandida albicanscauses lethal systemic infections because of its ability to grow and disseminate in a host. TheC. albicansplasma membrane is essential for virulence by acting as a protective barrier and through its key roles in interfacing with the environment, secretion of virulence factors, morphogenesis, and cell wall synthesis. Difficulties in studying hydrophobic membranes have limited the understanding of how plasma membrane organization contributes to its function and to the actions of antifungal drugs. Therefore, the role of the recently discovered plasma membrane subdomains termed the membrane compartment containing Can1 (MCC) was analyzed by assessing the virulence of asur7Δ mutant. Sur7 is an integral membrane protein component of the MCC that is needed for proper localization of actin, morphogenesis, cell wall synthesis, and responding to cell wall stress. MCC domains are stable 300-nm-sized punctate patches that associate with a complex of cytoplasmic proteins known as an eisosome. Analysis of virulence-related properties of asur7Δ mutant revealed defects in intraphagosomal growth in macrophages that correlate with increased sensitivity to oxidation and copper. Thesur7Δ mutant was also strongly defective in pathogenesis in a mouse model of systemic candidiasis. The mutant cells showed a decreased ability to initiate an infection and greatly diminished invasive growth into kidney tissues. These studies on Sur7 demonstrate that the plasma membrane MCC domains are critical for virulence and represent an important new target for the development of novel therapeutic strategies.IMPORTANCECandida albicans, the most common human fungal pathogen, causes lethal systemic infections by growing and disseminating in a host. The plasma membrane plays key roles in enablingC. albicansto growin vivo, and it is also the target of the most commonly used antifungal drugs. However, plasma membrane organization is poorly understood because of the experimental difficulties in studying hydrophobic components. Interestingly, recent studies have identified a novel type of plasma membrane subdomain in fungi known as the membrane compartment containing Can1 (MCC). Cells lacking the MCC-localized protein Sur7 display broad defects in cellular organization and response to stressin vitro. Consistent with this,C. albicanscells lacking theSUR7gene were more susceptible to attack by macrophages than cells with the gene and showed greatly reduced virulence in a mouse model of systemic infection. Thus, Sur7 and other MCC components represent novel targets for antifungal therapy.

scholarly journals pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans

2017 ◽  
Vol 8 ◽  
Author(s):  
Julien Chaillot ◽  
Faiza Tebbji ◽  
Carlos García ◽  
Hugo Wurtele ◽  
René Pelletier ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Pathogen ◽  
Human Fungal Pathogen

scholarly journals Pmt-Mediated O Mannosylation Stabilizes an Essential Component of the Secretory Apparatus, Sec20p, in Candida albicans

2004 ◽  
Vol 3 (5) ◽  
pp. 1164-1168 ◽  
Author(s):  
Yvonne Weber ◽  
Stephan K.-H. Prill ◽  
Joachim F. Ernst
Keyword(s):  
Endoplasmic Reticulum ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Wild Type ◽  
Rapid Degradation ◽  
Vesicle Traffic ◽  
Human Fungal Pathogen ◽  
Low Levels ◽  
Lumenal Domain ◽  
Secretory Apparatus

ABSTRACT Sec20p is an essential endoplasmic reticulum (ER) membrane protein in yeasts, functioning as a tSNARE component in retrograde vesicle traffic. We show that Sec20p in the human fungal pathogen Candida albicans is extensively O mannosylated by protein mannosyltransferases (Pmt proteins). Surprisingly, Sec20p occurs at wild-type levels in a pmt6 mutant but at very low levels in pmt1 and pmt4 mutants and also after replacement of specific Ser/Thr residues in the lumenal domain of Sec20p. Pulse-chase experiments revealed rapid degradation of unmodified Sec20p (38.6 kDa) following its biosynthesis, while the stable O-glycosylated form (50 kDa) was not formed in a pmt1 mutant. These results suggest a novel function of O mannosylation in eukaryotes, in that modification by specific Pmt proteins will prevent degradation of ER-resident membrane proteins via ER-associated degradation or a proteasome-independent pathway.

scholarly journals The 5’ untranslated region of theEFG1transcript promotes its translation to regulate hyphal morphogenesis inCandida albicans

2018 ◽  
Author(s):  
Prashant R. Desai ◽  
Klaus Lengeler ◽  
Mario Kapitan ◽  
Silas Matthias Janßen ◽  
Paula Alepuz ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Regulatory Mechanisms ◽  
Untranslated Regions ◽  
Regulatory Sequence ◽  
Transcriptional Level ◽  
Human Fungal Pathogen ◽  
Hyphal Morphogenesis ◽  
Cellular Morphogenesis ◽  
Incandida Albicans

ABSTRACTExtensive 5’ untranslated regions (UTR) are a hallmark of transcripts determining hyphal morphogenesis inCandida albicans.The major transcripts of theEFG1gene, which are responsible for cellular morphogenesis and metabolism, contain a 5’ UTR of up to 1170 nt. Deletion analyses of the 5’ UTR revealed a 218 nt sequence that is required for production of the Efg1 protein and its functions in filamentation, without lowering the level and integrity of theEFG1transcript. Polysomal analyses revealed that the 218 nt 5’ UTR sequence is required for efficient translation of the Efg1 protein. Replacement of theEFG1ORF by the heterologous reporter geneCaCBGlucconfirmed the positive regulatory importance of the identified 5’ UTR sequence. In contrast to other reported transcripts containing extensive 5’ UTR sequences, these results indicate the positive translational function of the 5’ UTR sequence in theEFG1transcript, which is observed in context of the nativeEFG1promoter. The results suggest that the 5’ UTR recruits regulatory factors, possibly during emergence of the native transcript, which aid in translation of theEFG1transcript.IMPORTANCEMany of the virulence traits that makeCandida albicansan important human fungal pathogen are regulated on a transcriptional level. Here we report an important regulatory contribution of translation, which is exerted by the extensive 5’ untranslated regulatory sequence (5’ UTR) of the transcript for the protein Efg1, which determines growth, metabolism and filamentation in the fungus. Presence of the 5’ UTR is required for efficient translation of Efg1, to promote filamentation. Because transcripts for many relevant regulators contain extensive 5’ UTR sequences, it appears that virulence ofC. albicansdepends on the combination of transcriptional and translation regulatory mechanisms.

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