scholarly journals Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

2021 ◽  
Author(s):  
Tomye L Ollinger ◽  
Bao Vu ◽  
Daniel Murante ◽  
Josie Parker ◽  
Lucia Simonicova ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Genetic Interaction ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Negative Regulator ◽  
Ergosterol Biosynthesis ◽  
Loss Of Function ◽  
Candida Spp ◽  
Ergosterol Biosynthesis Inhibitors ◽  
Positive Regulators

Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress induced transcription factors such as Upc2 and Upc2A as well as homologs of Sterol Response Element Binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other Candida spp., we used a serial passaging strategy to isolate suppressors of the fluconazole hypersusceptibility of a upc2AΔ deletion mutant. This led to the identification of loss of function mutants in two genes: ROX1, the homolog of a hypoxia gene transcriptional suppressor in Saccharomyces cerevisiae, and CST6, a transcription factor that is involved in the regulation of carbon dioxide response in C. glabrata. Here, we describe a detailed analysis of the genetic interaction of ROX1 and UPC2A. In the presence of fluconazole, loss of Rox1 function restores ERG11 expression to the upc2AΔ mutant and inhibits the expression of ERG3 and ERG6, leading to increased levels or ergosterol and decreased levels of the toxic sterol, 14α methyl-ergosta-8,24(28)-dien-3β, 6α-diol, relative to upc2AΔ. Our observations establish that Rox1 is a negative regulator of ERG gene biosynthesis and indicate that a least one additional positive transcriptional regulator of ERG gene biosynthesis must be present in C. glabrata.

scholarly journals Loss-of-Function ROX1 Mutations Suppress the Fluconazole Susceptibility of upc2A Δ Mutation in Candida glabrata, Implicating Additional Positive Regulators of Ergosterol Biosynthesis

mSphere ◽  
2021 ◽  
Vol 6 (6) ◽  
Author(s):  
Tomye L. Ollinger ◽  
Bao Vu ◽  
Daniel Murante ◽  
Josie E. Parker ◽  
Lucia Simonicova ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Ergosterol Biosynthesis ◽  
Loss Of Function ◽  
Content Type ◽  
Cellular Pathway ◽  
Positive Regulators

Candida glabrata is one of the most important human fungal pathogens and has reduced susceptibility to azole-class inhibitors of ergosterol biosynthesis. Although ergosterol is the target of two of the three classes of antifungal drugs, relatively little is known about the regulation of this critical cellular pathway.

The Regulatory Function of the Molecular Chaperone Hsp90 in the Cell Wall Integrity of Pathogenic Fungi

2018 ◽  
Vol 16 (1) ◽  
pp. 44-53
Author(s):  
Marina Campos Rocha ◽  
Camilla Alves Santos ◽  
Iran Malavazi
Keyword(s):  
Cell Wall ◽  
Antifungal Therapy ◽  
Molecular Chaperone ◽  
Regulatory Protein ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Hsp90 Inhibition

Different signaling cascades including the Cell Wall Integrity (CWI), the High Osmolarity Glycerol (HOG) and the Ca2+/calcineurin pathways control the cell wall biosynthesis and remodeling in fungi. Pathogenic fungi, such as Aspergillus fumigatus and Candida albicans, greatly rely on these signaling circuits to cope with different sources of stress, including the cell wall stress evoked by antifungal drugs and the host’s response during infection. Hsp90 has been proposed as an important regulatory protein and an attractive target for antifungal therapy since it stabilizes major effector proteins that act in the CWI, HOG and Ca2+/calcineurin pathways. Data from the human pathogen C. albicans have provided solid evidence that loss-of-function of Hsp90 impairs the evolution of resistance to azoles and echinocandin drugs. In A. fumigatus, Hsp90 is also required for cell wall integrity maintenance, reinforcing a coordinated function of the CWI pathway and this essential molecular chaperone. In this review, we focus on the current information about how Hsp90 impacts the aforementioned signaling pathways and consequently the homeostasis and maintenance of the cell wall, highlighting this cellular event as a key mechanism underlying antifungal therapy based on Hsp90 inhibition.

scholarly journals Synthesis, Characterization and in Vitro Antifungal Effect of Some Butyltin(IV) N-substituted 2-aminoethanethiolates

2001 ◽  
Vol 8 (3) ◽  
pp. 165-169 ◽  
Author(s):  
A. Smicka ◽  
V. Buchta ◽  
K. Handlir
Keyword(s):  
Candida Glabrata ◽  
Pathogenic Fungi ◽  
Trichophyton Mentagrophytes ◽  
Candida Krusei ◽  
Antifungal Drugs ◽  
Antifungal Effect ◽  
Absidia Corymbifera ◽  
Structure Activity ◽  
Trichosporon Beigelii

Six new N-substituted di- and tributyltin 2-aminoethanethiolates (cysteaminates) have been prepared and characterised by H1, C13 and S119n NMR spectroscopy. All these compounds exhibit a good in vitro antifungal effect against selected types of human pathogenic fungi (Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, Trichosporon beigelii, Aspergillus fumigatus, Absidia corymbifera, Trichophyton mentagrophytes) and their activity is comparable with that of some antifungal drugs commonly used in the clinical use like ketoconazole. The structure-activity relationships in these compounds are discussed.

scholarly journals Multiple mechanisms impact fluconazole resistance of mutant Erg11 proteins in Candida glabrata

2021 ◽  
Author(s):  
Bao Vu ◽  
W. Scott Moye-Rowley
Keyword(s):  
Transcription Factor ◽  
Candida Glabrata ◽  
Double Mutant ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Growth Defects

Azoles remain the most common used antifungal drugs for invasive candidiasis worldwide. They specifically inhibit the fungal lanosterol a-14 demethylase enzyme, which is commonly referred to as Erg11 in fungi. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. Many Candida species, such as Candida albicans, develop mutations in this enzyme which reduces the azole binding affinity and results in increased azole resistance. Candida glabrata is also a pathogenic yeast that has a low intrinsic susceptibility to azole drugs and easily develops elevated resistance. These azole resistant mutations are almost exclusively found to cause hyperactivity of the Pdr1 transcription factor and rarely lie within the ERG11 gene. Here, we generated C. glabrata ERG11 mutations that were analogous to azole resistance associated mutations in C. albicans ERG11. Three different Erg11 forms (Y141H, S410F, and the corresponding double mutant (DM)) conferred azole resistance in C. glabrata with the DM Erg11 form causing the strongest phenotype. The DM Erg11 also induced cross-resistance to amphotericin B and caspofungin. The azole resistance caused by the DM allele of ERG11 imposed a fitness cost that was not observed with hyperactive PDR1 alleles. These data support the view that C. glabrata does not typically acquire ERG11 mutations owing to growth defects associated with these lesions while hyperactive PDR1 alleles have no obvious growth issues. Understanding the physiology linking ergosterol biosynthesis with Pdr1-mediated regulation of azole resistance is crucial for ensuring the continued efficacy of azole drugs against C. glabrata.

scholarly journals A Computational Approach to Predict the Molecular Drug Targets Against Candida glabrata

2021 ◽  
Vol 14 (4) ◽  
pp. 1946-1955
Author(s):  
Priyanka Sirari
Keyword(s):  
Green Tea ◽  
In Silico ◽  
Candida Glabrata ◽  
Drug Targets ◽  
Antifungal Drugs ◽  
High Rate ◽  
Ergosterol Biosynthesis ◽  
Drug Candidates ◽  
Beneficial Effects ◽  
Potent Drug

Non- albicans Candida (NAC) species are responsible for 35-65% of all candidaemias in the general population and are associated with a high rate of morbidity and mortality (about 15% to 35%). The availability of few commercially used antifungal drugs against candidiasis and rapid emergences of antibiotic resistance among NAC species has significantly contributed to their increased global outbreak. Green tea is known for its multi-beneficial effects including antimicrobial potential against Candida. The present study investigated the molecular drug targets of green tea phytocompounds against inhibition of ergosterol biosynthesis in Candida glabrata using in silico tools.The molecular interaction was studied between ligands and essential proteins participating in ergosterol biosynthesis in C. glabrata using autodockvina software. The protein validation and homology modeling estimation were determined by the SWISS MODEL workspace. The Drug likeness study of all the test ligands was performed using SwissADME, while the toxicity of test compounds was analyzed using the admetSAR 2.0 version.The in silico analyses identified Rutin, Chlorogenic acid, Coumaroylquinic acid, Quercetin, Epigallocatechingallate as the potent phytocompounds with significant molecular binding with Erg 6, Erg 27, Erg 8, Erg 7, Erg 24 respectively. The ADMET data suggested an absence of the CYP2 inhibitors indicating the metabolism of all the tested drug candidates in the intestine and liver.The present study highlighted the possible drug targets of green tea phytocompounds against ergosterol biosynthesis protein in C. glabrata. It is pertinent that the current study has provided preliminary breakthroughs which could lead to exploring their avenues in potent drug development against NAC species.

scholarly journals Role of Candida glabrata as nosocomial pathogen and its susceptibility to Fluconazole, Voriconazole, Caspofungin, Micafungin and Amphotericin B

Bionatura ◽  
2021 ◽  
Vol 3 (3) ◽  
pp. 2001-2008
Author(s):  
Teeba Hashim Mohammed ◽  
Mohsen Hashim Risan ◽  
Mohammed Kadhom ◽  
Emad Yousif
Keyword(s):  
Biofilm Formation ◽  
Candida Glabrata ◽  
Bloodstream Infections ◽  
Antifungal Drugs ◽  
Candida Spp ◽  
Minimum Fungicidal Concentration ◽  
Weak Minimum ◽  
Different Types ◽  
Chromogenic Agar

Candida has different types that could cause bloodstream infections. A total number of 150 samples were collected from candidemia patients and examined. The Candida spp. Species isolated from blood samples were analysed. These were identified by culturing the species using different media, namely the chromogenic agar test. Then, the virulence factors of all samples were tested. The Candida glabrata isolates were tested with six commercial antifungal drugs. C. glabrata 67 (44.6%), C. albicans 34 (22.6%), C. krusei 18 (12%), C. tropicalis 17 (11.3%), and C. parasilosis 14 (9.3%). the production of phospholipase ranged between 0.63-0.99 mm. It was found that 96% of the species showed phospholipase activity in aerobic conditions. The protease activities of Candida spp. Isolates were experimentally tested by area of inhibition around the colonies, where 59.3% had the double (++) protease activity, 31.4% with (+) grade, and 9.3% had (–) grade or clear zone around the colony. The hemolytic capacity ranged from 0.69-0.89 in the optimum aerobic environments. Finally, 38.33% of the isolated Candida spp. were positive and 61.67% negative for biofilm formation. Out of the total positive Candida spp. for biofilm formation, 21.73% were strong biofilm producers, and 78.27% were weak. Minimum fungicidal concentration (MFC) of Fluconazole for C. glabrata isolates was not appropriate (NA) due to the occurrence of low inhibition tested for species. Micafungin exhibited the lowest fungicidal activity against C. glabrata ranging from 0.03 - 0.125, while Fluconazole showed the highest.

scholarly journals In Vitro Activities of Posaconazole (Sch 56592) Compared with Those of Itraconazole and Fluconazole against 3,685 Clinical Isolates of Candida spp. andCryptococcus neoformans

2001 ◽  
Vol 45 (10) ◽  
pp. 2862-2864 ◽  
Author(s):  
M. A. Pfaller ◽  
S. A. Messer ◽  
R. J. Hollis ◽  
R. N. Jones
Keyword(s):  
Candida Glabrata ◽  
Fungal Pathogens ◽  
Clinical Laboratory ◽  
Antifungal Drugs ◽  
National Committee ◽  
Broth Microdilution ◽  
Test Medium ◽  
Candida Spp ◽  
Medical Centers

ABSTRACT Posaconazole is a new investigational triazole with broad-spectrum antifungal activity. The in vitro activities of posaconazole were compared with those of itraconazole and fluconazole against 3,685 isolates of Candida spp. (3,312 isolates) and C. neoformans (373 isolates) obtained from over 70 different medical centers worldwide. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards method using RPMI 1640 as the test medium. Posaconazole was very active against all Candida spp. (MIC at which 90% of the isolates were inhibited [MIC90], 0.5 μg/ml; 97% of MICs were ≤1 μg/ml) and C. neoformans(MIC90, 0.5 μg/ml; 100% of MICs were ≤1 μg/ml).Candida albicans was the most susceptible species ofCandida (MIC90, 0.06 μg/ml), andCandida glabrata was the least susceptible (MIC90, 4 μg/ml). Posaconazole was more active than itraconazole and fluconazole against all Candida spp. and C. neoformans. These results provide further evidence for the spectrum and potency of posaconazole against a large and geographically diverse collection of clinically important fungal pathogens.

scholarly journals Antifungal Activity and Mechanism of Action of Different Parts of Myrtus communis Growing in Saudi Arabia against Candida Spp.

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Abdullah A. Alyousef
Keyword(s):  
Saudi Arabia ◽  
Natural Products ◽  
Antifungal Activity ◽  
Candida Glabrata ◽  
Candida Parapsilosis ◽  
Antifungal Drugs ◽  
Root Extract ◽  
Myrtus Communis ◽  
Leaf Extracts ◽  
Candida Spp

Discovering new antifungal drugs from natural products is a key target for the treatment of infections, such as candidiasis and other Candida-related infections. As current therapeutic drugs for the treatment of infections, such as candidiasis and other Candida-related infections, have adverse effects on human health, discovering new antifungal drugs from natural products is urgently needed. The objective of this study was to evaluate the antifungal activity of the methanolic and sodium phosphate buffer extracts derived from various parts of Myrtus communis, a plant that is traditionally used in Saudi Arabia, against Candida albicans (ATCC 10213), Candida glabrata (ATCC 2001), Candida kefyr (ATCC 66028), Candida parapsilosis (ATCC 22019), and Candida tropicalis (ATCC 750). A well diffusion assay was performed to assess the antifungal activity through the measurement of the zone of inhibition. Of the extracts, those extracted with methanol from the roots and leaves displayed strong inhibitory activity against Candida glabrata ( 23.5 ± 0.12 and 20.7 ± 0.22 , respectively), at 50 mg/ml, with 5 mg/ml fluconazole administered as the standard control. The minimal inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values were 12.5 mg/ml and 25 mg/ml for the M. communis root extract and 25 mg/ml and 50 mg/ml for the M. communis leaf extract against Candida glabrata. The results were confirmed by scanning electron microscopy (SEM) imaging of the control and treated strains of Candida glabrata. Based on SEM, these extracts could alter the morphology and cause loss of cell integrity. The effect of M. communis root and leaf extracts on Candida cells was also determined by measuring the absorbance at 260 nm after treatment for 1 h at 37°C. Interestingly, the 260 nm absorbing material was higher in Candida glabrata than in the resistant strain, Candida parapsilosis (ATCC 22019). Based on our findings, the crude methanolic extract of M. communis roots and leaves exhibited good antifungal activity against the Candida glabrata strain. SEM results and estimation of the 260 nm absorbance material proved that the extract might act on the cell wall and cell membrane of Candida cells, further leading to cell death.

scholarly journals Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/β-catenin activity

2003 ◽  
Vol 162 (5) ◽  
pp. 889-898 ◽  
Author(s):  
Trudi A. Westfall ◽  
Ryan Brimeyer ◽  
Jen Twedt ◽  
Jean Gladon ◽  
Andrea Olberding ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Cell Movement ◽  
Genetic Evidence ◽  
Negative Regulator ◽  
Axis Formation ◽  
Loss Of Function ◽  
Antagonistic Interaction ◽  
Function Defect

We provide genetic evidence defining a role for noncanonical Wnt function in vertebrate axis formation. In zebrafish, misexpression of Wnt-4, -5, and -11 stimulates calcium (Ca2+) release, defining the Wnt/Ca2+ class. We describe genetic interaction between two Wnt/Ca2+ members, Wnt-5 (pipetail) and Wnt-11 (silberblick), and a reduction of Ca2+ release in Wnt-5/pipetail. Embryos genetically depleted of both maternal and zygotic Wnt-5 product exhibit cell movement defects as well as hyperdorsalization and axis-duplication phenotypes. The dorsalized phenotypes result from increased β-catenin accumulation and activation of downstream genes. The Wnt-5 loss-of-function defect is consistent with Ca2+ modulation having an antagonistic interaction with Wnt/β-catenin signaling.

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