Aspergillus fumigatus
 ffmA
 Encodes a C
 2
 H
 2
 -Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth

Paul, Sanjoy; Bowyer, Paul; Bromley, Michael; Moye‐Rowley, W. Scott

doi:10.1128/msphere.00938-21

Cited by 5 publications

(25 citation statements)

References 26 publications

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“…It is worth to note that mutations in cyp51A gene associated with azole resistance are well known. However, different studies have been recently reported that some other gene loci including ATP-Binding Cassette Transporters ( Cdr1B ) , AtrR, Hmg1, HapE and FfmA are required for wild-type azole resistance in A. fumigatus as the most studied species in Aspergillus genus [ 17 , 18 , 19 , 20 , 21 ]. Likewise, it was suggested that the most common azole resistance allele currently described is a linked change corresponding to a change in the coding sequence of cyp51A and a duplication of a 34-bp region in the promoter leading to a tandem repeat [ 40 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…In response to triazoles acting on the locus of cyp51A and cyp51B genes, resulting mutation manifests as a non-synonymous substitution that alters the sequence of encoded proteins and thus resistant mutants are aroused [ 15 , 16 ]. However, mutation in non- cyp 51 gene including ATP-binding cassette transporters ( Cdr1B or abcG1 ) , AtrR, Hmg1, HapE and FfmA gene loci have been recently reported [ 17 , 18 , 19 , 20 , 21 ]. In recent years, whole genome sequencing (WGS) and bioinformatics methodologies have gained traction in the diagnostic field as potent appliances for detecting antifungal resistance in medical mycology [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

Nargesi

Valadan

Abastabar

et al. 2022

JoF

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The antifungal resistance in non-fumigatus Aspergillus spp., as well as Aspergillus fumigatus, poses a major therapeutic challenge which affects the entire healthcare community. Mutation occurrence of cyp51 gene paralogs is the major cause of azole resistance in Aspergillus spp.,. To obtain a full map of genomic changes, an accurate scan of the entire length of the Aspergillus genome is necessary. In this study, using whole genome sequencing (WGS) technique, we evaluated the mutation in cyp51A, cyp51B, Cdr1B, AtrR, Hmg1, HapE and FfmA genes in different clinical isolates of Aspergillus fumigatus, Aspergillus niger, Aspergillus tubingensis, Aspergillus welwitschiae and Aspergillus terreus which responded to minimum inhibitory concentrations of itraconazole above 16 µg mL−1. We found different nonsynonymous mutations in the cyp51A, cyp51B, Cdr1B, AtrR, Hmg1, HapE and FfmA gene loci. According to our findings, Aspergillus species isolated from different parts of the world may represent different pattern of resistance mechanisms which may be revealed by WGS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

Nargesi

Valadan

Abastabar

et al. 2022

JoF

View full text Add to dashboard Cite

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“…A screen of the library of A. fumigatus transcription factor gene disruptions led to the identification of a C2H2 protein called FfmA as a regulator of azole resistance, in part due to its effect on transcription of the abcG1 gene ( Furukawa et al . 2020 ; Paul, Bowyer, et al . 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…2019 ). An ffmAΔ strain exhibited very low expression of abcG1 , a phenotype that could be suppressed when AtrR was expressed from the strong hspA promoter ( Paul, Bowyer, et al . 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Interactions between the transcription factors FfmA and AtrR are required to properly regulate gene expression in the fungus Aspergillus fumigatus

Paul,

Stamnes,

Moye-Rowley

2023

G3: Genes, Genomes, Genetics

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Transcriptional regulation of azole resistance in the filamentous fungus Aspergillus fumigatus is a key step in development of this problematic clinical phenotype. We and others have previously described a C2H2-containing transcription factor called FfmA that is required for normal levels of voriconazole susceptibility. Null alleles of ffmA exhibit a strongly compromised growth rate even in the absence of any external stress. Here we employ an acutely repressible doxycycline-off form of ffmA to rapidly deplete FfmA protein from the cell. Using this approach, we carried out RNA-seq analyses to probe the transcriptome cells acutely deprived of FfmA. 2000 genes were differentially expressed upon acute depletion of FfmA, illustrating the broad transcriptomic effect of this factor. Interestingly, the transcriptome changes observed upon this acute depletion of FfmA expression only shared limited overlap with those found in an ffmAΔ null strain analyzed by others. Chromatin immunoprecipitation coupled with high throughput DNA sequencing analysis (ChIP-seq) identified 530 genes that were bound by FfmA. More than 300 of these genes were also bound by AtrR, a transcription factor important in azole drug resistance, demonstrating striking regulatory overlap with FfmA. However, while AtrR is an upstream activation protein with known specificity, our data suggest that FfmA is a chromatin-associated factor that binds DNA in a manner dependent on other factors. We provide evidence that AtrR and FfmA interact in the cell and show reciprocal expression modulation. Interaction of AtrR and FfmA is required for normal gene expression in A. fumigatus.

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Mechanisms of Resistance to Antifungal Agents

Perlin

2023

ClinMicroNow

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This chapter focuses on the epidemiologic, biological, and molecular nature of antifungal drug resistance. Antifungal drug action and the host immune system often must work synergistically to control and clear an infection. “Microbiological resistance” refers to decreased susceptibility of a fungal strain to an antifungal agent, which is reflected in standardized antifungal in vitro susceptibility testing relative to susceptible standard reference strains, as defined by the Clinical Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing. The azole antifungal agents are the most prominent example of drug selection for less susceptible species. The polyene drug amphotericin is fungicidal, and resistance rarely occurs. Fungi encode numerous putative drug efflux transporters that have the potential to influence susceptibility to azole antifungal agents by reducing the effective cellular concentration of drugs below their inhibitory threshold. Biofilms are among the most prevalent forms of microbial growth in nature.

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Aspergillus fumigatus ffmA Encodes a C ₂ H ₂ -Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth

Abstract: Infections associated with azole-resistant forms of the primary human pathogen Aspergillus fumigatus are associated with poor outcomes in patient populations. This makes analysis of the mechanisms underlying azole resistance of A. fumigatus a high priority.

Cited by 5 publications

References 26 publications

A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

Interactions between the transcription factors FfmA and AtrR are required to properly regulate gene expression in the fungus Aspergillus fumigatus

Mechanisms of Resistance to Antifungal Agents

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Aspergillus fumigatus ffmA Encodes a C 2 H 2 -Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth

Abstract: Infections associated with azole-resistant forms of the primary human pathogen Aspergillus fumigatus are associated with poor outcomes in patient populations. This makes analysis of the mechanisms underlying azole resistance of A. fumigatus a high priority.

Cited by 5 publications

References 26 publications

A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

A Whole Genome Sequencing-Based Approach to Track down Genomic Variants in Itraconazole-Resistant Species of Aspergillus from Iran

Interactions between the transcription factors FfmA and AtrR are required to properly regulate gene expression in the fungus Aspergillus fumigatus

Mechanisms of Resistance to Antifungal Agents

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Aspergillus fumigatus ffmA Encodes a C ₂ H ₂ -Containing Transcriptional Regulator That Modulates Azole Resistance and Is Required for Normal Growth