Paralogous Cyp51s mediate the differential sensitivity of <i>Fusarium oxysporum</i> to sterol demethylation inhibitors

Zheng, Bangxian; Yan, Leiyan; Liang, Wenxing; Yang, Qiwen

doi:10.1002/ps.5127

Cited by 26 publications

(32 citation statements)

References 53 publications

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“…The evolution of the gene families that contain genes involved in drug resistance might also give us clues on how drug resistance evolves in fungal populations; previous studies (Hawkins et al, 2014;Zheng et al, 2019) report two paralogs of cyp51 in diverse species, including A. fumigatus, A. nidulans, Penicillium digitatum, and Magnaporthe oryzae, while Fusarium graminearum, A. flavus, and A. oryzae have three cyp51 genes (Dudakova et al, 2017). Recently, a study proposed the existence of cyp51C gene arising from a duplication in cyp51B in A. terreus and A. carbonarius (Perez-Cantero et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

et al. 2020

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Fungal pathogens are a global threat to human health. For example, fungi from the genus Aspergillus cause a spectrum of diseases collectively known as aspergillosis. Most of the >200,000 life-threatening aspergillosis infections per year worldwide are caused by Aspergillus fumigatus. Recently, molecular typing techniques have revealed that aspergillosis can also be caused by organisms that are phenotypically similar to A. fumigatus but genetically distinct, such as Aspergillus lentulus and Aspergillus fumigatiaffinis. Importantly, some of these so-called cryptic species are thought to exhibit different virulence and drug susceptibility profiles than A. fumigatus, however, our understanding of their biology and pathogenic potential has been stymied by the lack of genome sequences and phenotypic profiling of multiple clinical strains. To fill this gap, we phenotypically characterized the virulence and drug susceptibility of 15 clinical strains of A. fumigatus, A. lentulus, and A. fumigatiaffinis from Spain and sequenced their genomes. We found heterogeneity in drug susceptibility across species and strains. We further found heterogeneity in virulence within each species but no significant differences in the virulence profiles between the three species. Genes known to influence drug susceptibility (cyp51A and fks1) vary in paralog number and sequence among these species and strains and correlate with differences in drug susceptibility. Similarly, genes known to be important for virulence in A. fumigatus showed variability in number of paralogs across strains and across species. Characterization of the genomic similarities and differences of clinical strains of A. lentulus, A. fumigatiaffinis, and A. fumigatus that vary in disease-relevant traits will advance our understanding of the variance in pathogenicity between Aspergillus species and strains that are collectively responsible for the vast majority of aspergillosis infections in humans.

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Section: Discussionmentioning

confidence: 99%

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

et al. 2020

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“…Recent studies have shown that Fusarium spp. also have three Cyp51 paralogues (Cyp51A, -B, and -C), with Cyp51C being unique to the genus [ 44 , 45 ]. However, Fusarium spp.…”

Section: Discussionmentioning

confidence: 99%

Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus

Lúcio

González-Jiménez

Rivero-Menéndez

et al. 2020

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Infections caused by Aspergillus species are being increasingly reported. Aspergillus flavus is the second most common species within this genus causing invasive infections in humans, and isolates showing azole resistance have been recently described. A. flavus has three cyp51-related genes (cyp51A, cyp51B, and cyp51C) encoding 14-α sterol demethylase-like enzymes which are the target of azole drugs. In order to study triazole drug resistance in A. flavus, three strains showing reduced azole susceptibility and 17 azole susceptible isolates were compared. The three cyp51-related genes were amplified and sequenced. A comparison of the deduced Cyp51A, Cyp51B, and Cyp51C protein sequences with other protein sequences from orthologous genes in different filamentous fungi led to a protein identity that ranged from 50% to 80%. Cyp51A and Cyp51C presented several synonymous and non-synonymous point mutations among both susceptible and non-susceptible strains. However, two amino acid mutations were present only in two resistant isolates: one strain harbored a P214L substitution in Cyp51A, and another a H349R in Cyp51C that also showed an increase of cyp51A and cyp51C gene expression compared to the susceptible strain ATCC2004304. Isolates that showed reduced in vitro susceptibility to clinical azoles exhibited a different susceptibility profile to demethylation inhibitors (DMIs). Although P214L substitution might contribute to azole resistance, the role of H349R substitution together with changes in gene expression remains unclear.

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“…Aspergilli have two CYP51 orthologues (CYP51A and CYP51B) (Mellado et al, 2001) whereas Fusarium spp. have three CYP51 orthologues (CYP51A, CYP51B and CYP51C) (Becher et al, 2011;Zheng et al, 2019;James et al, 2020). The CYP51C orthologue is a unique characteristic of this fungal genus.…”

Section: Introductionmentioning

confidence: 99%

“…The CYP51C orthologue is a unique characteristic of this fungal genus. CYP51A and CYP51B are sterol 14-α demethylases, but the function of CYP51C remains unknown (Fan et al, 2013;Zheng et al, 2019). We have recently reported a 23 bp CYP51A promoter deletion that was associated with increased VRC resistance in both clinical and environmental FSSC isolates (James et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

PDR Transporter ABC1 Is Involved in the Innate Azole Resistance of the Human Fungal Pathogen Fusarium keratoplasticum

et al. 2021

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Fusarium keratoplasticum is arguably the most common Fusarium solani species complex (FSSC) species associated with human infections. Invasive fusariosis is a life-threatening fungal infection that is difficult to treat with conventional azole antifungals. Azole drug resistance is often caused by the increased expression of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG sub-family. Most investigations of Fusarium ABC transporters associated with azole antifungal drug resistance are limited to plant pathogens. Through the manual curation of the entire ABCG protein family of four FSSC species including the fully annotated genome of the plant pathogen Nectria haematococca we identified PDR transporters ABC1 and ABC2 as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of Fusarium keratoplasticum. An initial investigation of the transcriptional response of logarithmic phase F. keratoplasticum cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of ABC1 while ABC2 mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of F. keratoplasticum ABC1 and ABC2 in the genetically modified Saccharomyces cerevisiae host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although ABC1 and ABC2 were only moderately (20% and 10%, respectively) expressed compared to the Candida albicans multidrug efflux pump CDR1, overexpression of F. keratoplasticum ABC1 caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than CDR1. Our investigations suggest an important role for ABC1 orthologues in the innate azole resistance phenotype of FSSC species.

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Paralogous Cyp51s mediate the differential sensitivity of Fusarium oxysporum to sterol demethylation inhibitors

Abstract: FoCYP51A and FoCYP51B are responsible for sensitivity to different azoles. These findings have direct implications for fungicide application strategies of plant and human diseases caused by F. oxysporum. © 2018 Society of Chemical Industry.

Cited by 26 publications

References 53 publications

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

Genomic and Phenotypic Heterogeneity of Clinical Isolates of the Human Pathogens Aspergillus fumigatus, Aspergillus lentulus, and Aspergillus fumigatiaffinis

Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus

PDR Transporter ABC1 Is Involved in the Innate Azole Resistance of the Human Fungal Pathogen Fusarium keratoplasticum

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