azole tolerance
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2022 ◽  
Author(s):  
Rebekah J Kukurudz ◽  
Madison Chapel ◽  
Quinn Wonitowy ◽  
Abdul-Rahman Adamu Bukari ◽  
Brooke Sidney ◽  
...  

A number of in vitro studies have examined the acquisition of drug resistance to the triazole fluconazole, a first-line treatment for many Candida infections. Much less is known about posaconazole, a newer triazole. We conducted the first in vitro experimental evolution of replicates from eight diverse strains of C. albicans in a high level of the fungistatic drug posaconazole. Approximately half of the 132 evolved replicates survived 50 generations of evolution, biased towards some of the strain backgrounds. We found that although increases in drug resistance were rare, increases in drug tolerance (the slow growth of a subpopulation of cells in a level of drug above the resistance level) were common across strains. We also found that adaptation to posaconazole resulted in widespread cross-tolerance to other azole drugs. Widespread aneuploidy variation was also observed in evolved replicates from some strain backgrounds. Trisomy of chromosomes 3, 6, and R was identified in 11 of 12 whole-genome sequenced evolved SC5314 replicates. These findings document rampant evolved cross-tolerance among triazoles and highlight that increases in drug tolerance can evolve independently of drug resistance in a diversity of C. albicans strain backgrounds.


Author(s):  
Takahito Toyotome ◽  
Kenji Onishi ◽  
Mio Sato ◽  
Yoko Kusuya ◽  
Daisuke Hagiwara ◽  
...  

Azole resistance of Aspergillus fumigatus is a global problem. The major resistant mechanism is a cytochrome P 450 14-α sterol demethylase Cyp51A alteration such as mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerances and resistant mechanisms such as hmg1 (a 3-hydroxy-3-methylglutaryl-coenzyme-A reductase gene) mutation are known, few reports have described studies elucidating non-Cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three-round selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the obtained isolates and the parental strain revealed a non-synonymous mutation in MfsD for a major facilitator superfamily protein (Afu1g11820, R337L mutation) in all isolates. Furthermore, non-synonymous mutations in AgcA for a mitochondrial inner membrane aspartate/glutamate transporter (Afu7g05220, E535Stop mutation), UbcD for a ubiquitin-conjugating enzyme E2 (Afu3g06030, T98K mutation), AbcJ for an ABC transporter (Afu3g12220, G297E mutation), and RttA for a putative protein r esponsible for t ebuconazole t olerance (Afu7g04740, A83T mutation), were found in at least one isolate. Disruption of the agcA gene led to decreased susceptibility to azoles. Reconstruction of the A83T point mutation in RttA led to decreased susceptibility to azoles. Reversion of T98K mutation to wild type in UbcD led to decreased susceptibility to azoles. These results suggest that these mutations contribute to lowered susceptibility to medical azoles and agricultural azole fungicides.


2020 ◽  
Author(s):  
Takahito Toyotome ◽  
Kenji Onishi ◽  
Mio Sato ◽  
Yoko Kusuya ◽  
Daisuke Hagiwara ◽  
...  

AbstractAzole resistance of Aspergillus fumigatus is a global problem. The major resistant mechanism is a cyp51A alteration such as mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerances and resistant mechanisms such as hmg1 mutation are known, few reports describe studies elucidating non-cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three-round selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the obtained isolates and the parental strain revealed a non-synonymous mutation in MfsD (Afu1g11820, R337L mutation) in all isolates. Furthermore, non-synonymous mutations in AgcA (Afu7g05220, E535Stop mutation), UbcD (Afu3g06030, T98K mutation), AbcJ (Afu3g12220, G297E mutation), and RttA (Afu7g04740, A83T mutation), a protein responsible for tebuconazole tolerance, were found in at least one isolate. Clarification by constructing the MfsD R337L mutant suggests that the mutation contributes to azole tolerance. Disruption of the agcA gene and reconstruction of the A83T point mutation in RttA led to decreased susceptibility to azoles. The reversion of T98K mutation to wild type in UbcD led to the level of azole susceptibility comparable to the parental strain. These results suggest that these mutations contribute to lowered susceptibility to medical azoles and to agricultural azole fungicides.


mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Sang Hu Kim ◽  
Kali R. Iyer ◽  
Lakhansing Pardeshi ◽  
José F. Muñoz ◽  
Nicole Robbins ◽  
...  

2016 ◽  
Vol 12 (12) ◽  
pp. e1006106 ◽  
Author(s):  
Fabio Gsaller ◽  
Peter Hortschansky ◽  
Takanori Furukawa ◽  
Paul D. Carr ◽  
Bharat Rash ◽  
...  

2016 ◽  
pp. AAC.01034-16 ◽  
Author(s):  
Arturo Luna-Tapia ◽  
Hélène Tournu ◽  
Tracy L. Peters ◽  
Glen E. Palmer

The azole antifungals arrest fungal growth through inhibition of ergosterol biosynthesis. We recently reported that avps21Δ/Δmutant, deficient in membrane trafficking through the late endosome/pre-vacuolar compartment (PVC), continues to grow in the presence of the azoles, despite depletion of cellular ergosterol. Herein, we report that thevps21Δ/Δmutant exhibits less plasma membrane damage upon azole treatment than wild-type, as measured by the release of a cytoplasmic luciferase reporter into the culture supernatant. Our results also reveal that thevps21Δ/Δmutant has abnormal levels of intracellular Ca2+, and in the presence of fluconazole, enhanced expression of a calcineurin responsiveRTA2-GFPreporter. Furthermore, the azole tolerance phenotype of thevps21Δ/Δmutant is dependent upon both extracellular calcium levels and calcineurin activity. These findings underscore the importance of endosomal trafficking in determining the cellular consequences of azole treatment, and indicate that this may occur through modulation of calcium and calcineurin dependent responses.


2016 ◽  
Vol 12 (7) ◽  
pp. e1005775 ◽  
Author(s):  
Fabio Gsaller ◽  
Peter Hortschansky ◽  
Takanori Furukawa ◽  
Paul D. Carr ◽  
Bharat Rash ◽  
...  

2014 ◽  
Vol 58 (11) ◽  
pp. 6904-6912 ◽  
Author(s):  
Sanjoy Paul ◽  
Thomas B. Bair ◽  
W. Scott Moye-Rowley

ABSTRACTThe fungal pathogenCandida glabratais an emerging cause of candidiasis in part owing to its robust ability to acquire tolerance to the major clinical antifungal drug fluconazole. Similar to the related speciesCandida albicans,C. glabratamost typically gains azole tolerance via transcriptional induction of a suite of resistance genes, including a locus encoding an ABCG-type ATP-binding cassette (ABC) transporter that is referred to asCDR1inCandidaspecies. InC. glabrata,CDR1expression is controlled primarily by the activity of a transcriptional activator protein called Pdr1. Strains exhibiting reduced azole susceptibility often contain substitution mutations inPDR1that in turn lead to elevated mRNA levels of target genes with associated azole resistance. Pdr1 activity is also induced upon loss of the mitochondrial genome status and upon challenge by azole drugs. While extensive analyses of the transcriptional effects of Pdr1 have identified a number of genes that are regulated by this factor, we cannot yet separate direct from indirect target genes. Here we used chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-seq) to identify the promoters and associated genes directly regulated by Pdr1. These genes include many that are shared with the yeastSaccharomyces cerevisiaebut others that are unique toC. glabrata, including the ABC transporter-encoding locusYBT1, genes involved in DNA repair, and several others. These data provide the outline for understanding the primary response genes involved in production of Pdr1-dependent azole resistance inC. glabrata.


PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e79042 ◽  
Author(s):  
Ghada Abou Ammar ◽  
Reno Tryono ◽  
Katharina Döll ◽  
Petr Karlovsky ◽  
Holger B. Deising ◽  
...  

Yeast ◽  
2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Hana Culakova ◽  
Vladimira Dzugasova ◽  
Jana Perzelova ◽  
Yvetta Gbelska ◽  
Julius Subik

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