scholarly journals Antifungal Resistance in Candida auris: Molecular Determinants

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 568
Author(s):  
María Guadalupe Frías-De-León ◽  
Rigoberto Hernández-Castro ◽  
Tania Vite-Garín ◽  
Roberto Arenas ◽  
Alexandro Bonifaz ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Molecular Mechanisms ◽  
Efflux Pumps ◽  
Antifungal Resistance ◽  
Candida Auris ◽  
Fluconazole Resistance ◽  
Online Databases ◽  
Molecular Determinants ◽  
Erg Genes

Since Candida auris integrates strains resistant to multiple antifungals, research has been conducted focused on knowing which molecular mechanisms are involved. This review aims to summarize the results obtained in some of these studies. A search was carried out by consulting websites and online databases. The analysis indicates that most C. auris strains show higher resistance to fluconazole, followed by amphotericin B, and less resistance to 5-fluorocytosine and caspofungin. In C. auris, antifungal resistance to amphotericin B has been linked to an overexpression of several mutated ERG genes that lead to reduced ergosterol levels; fluconazole resistance is mostly explained by mutations identified in the ERG11 gene, as well as a higher number of copies of this gene and the overexpression of efflux pumps. For 5-fluorocytosine, it is hypothesized that the resistance is due to mutations in the FCY2, FCY1, and FUR1 genes. Resistance to caspofungin has been associated with a mutation in the FKS1 gene. Finally, resistance to each antifungal is closely related to the type of clade to which the strain belongs.

scholarly journals Experimental Evolution Identifies Adaptive Aneuploidy as a Mechanism of Fluconazole Resistance in Candida auris

2020 ◽  
Vol 65 (1) ◽  
pp. e01466-20
Author(s):  
Jian Bing ◽  
Tianren Hu ◽  
Qiushi Zheng ◽  
José F. Muñoz ◽  
Christina A. Cuomo ◽  
...  
Keyword(s):  
Experimental Evolution ◽  
Acquired Resistance ◽  
Basic Research ◽  
Antifungal Resistance ◽  
Missense Mutations ◽  
Candida Auris ◽  
Extra Copy ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Rapid Acquisition

ABSTRACTCandida auris is a newly emerging fungal pathogen of humans and has attracted considerable attention from both the clinical and basic research communities. Clinical isolates of C. auris are often resistant to one or more antifungal agents. To explore how antifungal resistance develops, we performed experimental evolution assays using a fluconazole-susceptible isolate of C. auris (BJCA001). After a series of passages through medium containing increasing concentrations of fluconazole, fungal cells acquired resistance. By sequencing and comparing the genomes of the parental fluconazole-susceptible strain and 26 experimentally evolved strains of C. auris, we found that a portion of fluconazole-resistant strains carried one extra copy of chromosome V. In the absence of fluconazole, C. auris cells rapidly became susceptible and lost the extra copy of chromosome V. Genomic and transcriptome sequencing (RNA-Seq) analyses indicate that this chromosome carries a number of drug resistance-related genes, which were transcriptionally upregulated in the resistant, aneuploid strains. Moreover, missense mutations were identified in the genes TAC1B, RRP6, and SFT2 in all experimentally evolved strains. Our findings suggest that the gain of an extra copy of chromosome V is associated with the rapid acquisition of fluconazole resistance and may represent an important evolutionary mechanism of antifungal resistance in C. auris.

scholarly journals A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Eva-Maria Mayr ◽  
Bernardo Ramírez-Zavala ◽  
Ines Krüger ◽  
Joachim Morschhäuser
Keyword(s):  
Transcription Factor ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Drug Resistant ◽  
Candida Auris ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Zinc Cluster ◽  
Genes Encoding

ABSTRACT The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism. IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast.

scholarly journals Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses

2020 ◽  
Author(s):  
Nancy A. Chow ◽  
José F. Muñoz ◽  
Lalitha Gade ◽  
Elizabeth Berkow ◽  
Xiao Li ◽  
...  
Keyword(s):  
Public Health ◽  
Population Structure ◽  
Healthcare Facility ◽  
Antifungal Resistance ◽  
Nosocomial Transmission ◽  
Phylogenetic Study ◽  
Candida Auris ◽  
Public Health Response ◽  
Fluconazole Resistance ◽  
Health Response

AbstractCandida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (Clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; Clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single healthcare facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 339 years; outbreak-causing clusters from Clades I, III, and IV originated 34-35 years ago. We observed high rates of antifungal resistance in Clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in Clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris.ImportanceIn less than a decade, C. auris has emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.

scholarly journals Antifungal Resistance: Specific Focus on Multidrug Resistance in Candida auris and Secondary Azole Resistance in Aspergillus fumigatus

2018 ◽  
Vol 4 (4) ◽  
pp. 129 ◽  
Author(s):  
Sevtap Arikan-Akdagli ◽  
Mahmoud Ghannoum ◽  
Jacques Meis
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Multidrug Resistant ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Current Status ◽  
Clinical Implications ◽  
Azole Resistance ◽  
Candida Auris

Antifungal resistance is a topic of concern, particularly for specific fungal species and drugs. Among these are the multidrug-resistant Candida auris and azole-resistant Aspergillus fumigatus. While the knowledge on molecular mechanisms of resistance is now accumulating, further data are also available for the clinical implications and the extent of correlation of in vitro resistance to clinical outcomes. This review article summarizes the epidemiology of C. auris infections, animal models focusing on the activity of novel antifungal compounds in C. auris infections, virulence factors, and the mechanisms of antifungal resistance for this multi-resistant Candida species. Regarding A. fumigatus, the significance of azoles in the treatment of A. fumigatus infections, reference methods available for the detection of resistance in vitro, molecular mechanisms of secondary azole resistance, routes of acquisition, and clinical implications of in vitro resistance are covered to provide guidance for the current status of azole resistance in A. fumigatus.

scholarly journals Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Nancy A. Chow ◽  
José F. Muñoz ◽  
Lalitha Gade ◽  
Elizabeth L. Berkow ◽  
Xiao Li ◽  
...  
Keyword(s):  
Public Health ◽  
Health Care ◽  
Population Structure ◽  
Antifungal Resistance ◽  
Nosocomial Transmission ◽  
Candida Auris ◽  
Public Health Response ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Health Response

ABSTRACT Candida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in more than 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 years ago. We observed high rates of antifungal resistance in clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris. IMPORTANCE In less than a decade, C. auris has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.

Antifungal Resistance Trends of Candida auris Clinical Isolates, New York-New Jersey, 2016-2020

2022 ◽  
Author(s):  
Shannon Kilburn ◽  
Gabriel Innes ◽  
Monica Quinn ◽  
Karen Southwick ◽  
Belinda Ostrowsky ◽  
...  
Keyword(s):  
New York ◽  
New Jersey ◽  
Amphotericin B ◽  
Regional Differences ◽  
Antifungal Resistance ◽  
Clinical Isolates ◽  
Candida Auris ◽  
Fluconazole Resistant ◽  
Echinocandin Resistance ◽  
Clinical Cases

About 55% of U.S. Candida auris clinical cases were reported from New York and New Jersey from 2016 through 2020. Nearly all New York-New Jersey clinical isolates (99.8%) were fluconazole resistant, and 50% were amphotericin B resistant. Echinocandin resistance increased from 0% to 4% and pan-resistance increased from 0 to <1% for New York C. auris clinical isolates but not for New Jersey, highlighting the regional differences.

scholarly journals Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
M. C. Arendrup ◽  
Anupam Prakash ◽  
Joseph Meletiadis ◽  
Cheshta Sharma ◽  
Anuradha Chowdhary
Keyword(s):  
Amphotericin B ◽  
Susceptibility Testing ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Quantitative Agreement ◽  
Anova Analysis ◽  
Candida Auris ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Multiple Comparison Test

ABSTRACT Candida auris is an emerging multidrug-resistant yeast. So far, all but two susceptibility testing studies have examined ≤50 isolates, mostly with the CLSI method. We investigated CLSI and EUCAST MICs for 123 C. auris isolates and eight antifungals and evaluated various methods for epidemiological cutoff (ECOFF) determinations. MICs (in milligrams per liter) were determined using CLSI method M27-A3, and the EUCAST E.Def 7.3. ANOVA analysis of variance with Bonferroni's multiple-comparison test and Pearson analysis were used on log2 MICs (significance at P values of <0.05). The percent agreement (within ±0 to ±2 2-fold dilutions) between the methods was calculated. ECOFFs were determined visually, statistically (using the ECOFF Finder program and MicDat1.23 software with 95% to 99% endpoints), and via the derivatization method (dECOFFs). The CLSI and EUCAST MIC distributions were wide, with several peaks for all compounds except amphotericin B, suggesting possible acquired resistance. Modal MIC, geometric MIC, MIC50, and MIC90 values were ≤1 2-fold dilutions apart, and no significant differences were found. The quantitative agreement was best for amphotericin B (80%/97% within ±1/±2 dilutions) and lowest for isavuconazole and anidulafungin (58%/76% to 75% within ±1/±2 dilutions). We found that 90.2%/100% of the isolates were amphotericin B susceptible based on CLSI/EUCAST methods, respectively (i.e., with MICs of ≤1 mg/liter), and 100%/97.6% were fluconazole nonsusceptible by CLSI/EUCAST (MICs > 2). The ECOFFs (in milligrams per liter) were similar across the three different methods for itraconazole (ranges for CLSI/EUCAST, 0.25 to 0.5/0.5 to 1), posaconazole (0.125/0.125 to 0.25), amphotericin B (0.25 to 0.5/1 to 2), micafungin (0.25 to 0.5), and anidulafungin (0.25 to 0.5/0.25 to 1). In contrast, the estimated ECOFFs were dependent on the method applied for voriconazole (1 to 32) and isavuconazole (0.125 to 4). CLSI and EUCAST MICs were remarkably similar and confirmed uniform fluconazole resistance and variable acquired resistance to the other agents.

scholarly journals The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

2020 ◽  
Vol 6 (3) ◽  
pp. 138 ◽  
Author(s):  
Amir Arastehfar ◽  
Cornelia Lass-Flörl ◽  
Rocio Garcia-Rubio ◽  
Farnaz Daneshnia ◽  
Macit Ilkit ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Candida Auris ◽  
Recent Emergence ◽  
Invasive Infections

Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

scholarly journals Mechanisms of Azole Resistance in Clinical Isolates of Candida glabrata Collected during a Hospital Survey of Antifungal Resistance

2005 ◽  
Vol 49 (2) ◽  
pp. 668-679 ◽  
Author(s):  
Maurizio Sanguinetti ◽  
Brunella Posteraro ◽  
Barbara Fiori ◽  
Stefania Ranno ◽  
Riccardo Torelli ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Candida Glabrata ◽  
Molecular Mechanisms ◽  
Efflux Pumps ◽  
Antifungal Resistance ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Azole Resistance ◽  
Relative Level ◽  
Fluconazole Resistant

ABSTRACT The increasing use of azole antifungals for the treatment of mucosal and systemic Candida glabrata infections has resulted in the selection and/or emergence of resistant strains. The main mechanisms of azole resistance include alterations in the C. glabrata ERG11 gene (CgERG11), which encodes the azole target enzyme, and upregulation of the CgCDR1 and CgCDR2 genes, which encode efflux pumps. In the present study, we evaluated these molecular mechanisms in 29 unmatched clinical isolates of C. glabrata, of which 20 isolates were resistant and 9 were susceptible dose dependent (S-DD) to fluconazole. These isolates were recovered from separate patients during a 3-year hospital survey for antifungal resistance. Four of the 20 fluconazole-resistant isolates were analyzed together with matched susceptible isolates previously taken from the same patients. Twenty other azole-susceptible clinical C. glabrata isolates were included as controls. MIC data for all the fluconazole-resistant isolates revealed extensive cross-resistance to the other azoles tested, i.e., itraconazole, ketoconazole, and voriconazole. Quantitative real-time PCR analyses showed that CgCDR1 and CgCDR2, alone or in combination, were upregulated at high levels in all but two fluconazole-resistant isolates and, to a lesser extent, in the fluconazole-S-DD isolates. In addition, slight increases in the relative level of expression of CgSNQ2 (which encodes an ATP-binding cassette [ABC] transporter and which has not yet been shown to be associated with azole resistance) were seen in some of the 29 isolates studied. Interestingly, the two fluconazole-resistant isolates expressing normal levels of CgCDR1 and CgCDR2 exhibited increased levels of expression of CgSNQ2. Conversely, sequencing of CgERG11 and analysis of its expression showed no mutation or upregulation in any C. glabrata isolate, suggesting that CgERG11 is not involved in azole resistance. When the isolates were grown in the presence of fluconazole, the profiles of expression of all genes, including CgERG11, were not changed or were only minimally changed in the resistant isolates, whereas marked increases in the levels of gene expression, particularly for CgCDR1 and CgCDR2, were observed in either the fluconazole-susceptible or the fluconazole-S-DD isolates. Finally, known ABC transporter inhibitors, such as FK506, were able to reverse the azole resistance of all the isolates. Together, these results provide evidence that the upregulation of the CgCDR1-, CgCDR2-, and CgSNQ2-encoded efflux pumps might explain the azole resistance in our set of isolates.

scholarly journals Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marjan Talebi ◽  
Mohsen Talebi ◽  
Tahereh Farkhondeh ◽  
Jesus Simal-Gandara ◽  
Dalia M. Kopustinskiene ◽  
...  
Keyword(s):  
Blood Cells ◽  
Molecular Mechanisms ◽  
Web Of Science ◽  
Experimental Studies ◽  
Protective Effects ◽  
Pharmacological Activities ◽  
Current Review ◽  
Mesh Terms ◽  
Online Databases ◽  
Anti Cancer

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies. Graphic abstract

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