Cyp51A mutations, Extrolite Profiles and Antifungal Susceptibility in Clinical and Environmental Isolates of the Aspergillus viridinutans Species Complex

Jessica J. Talbot*, Jens Christian Frisvad, Jacques F. Meis, Ferry Hagen, Paul E. Verweij, David E. Hibbs, Felcia Lai, Robert A. Samson, Sarah E. Kidd, Vanessa R. Barrs, Jos Houbraken

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

The past decade has seen an increase in aspergillosis in humans and animals due to Aspergillus viridinutans species complex members. Azole resistance is common to these infections, carrying a poor prognosis. Cyp51A gene mutations are the main cause of acquired azole resistance in Aspergillus fumigatus This study aimed to determine if azole-resistant phenotype in A. viridinutans complex members is associated with cyp51A mutations or extrolite profiles. The cyp51A gene of clinical and environmental isolates was amplified using novel primers, antifungal susceptibility was tested using Clinical Laboratory Standards Institute methodology and extrolite profiling was performed using agar plug extraction. Very high azole minimum inhibitory concentrations (MICs) were detected in 84% of the isolates (31/37). MICs of newer antifungals luliconazole and olorofim (F901318) were low for all isolates. Cyp51A sequences revealed 113 non-synonymous mutations compared to wild-type A. fumigatus M172A/V and D255G, previously associated with A. fumigatus azole resistance, were common amongst all isolates but were not correlated with azole MICs. Two environmental isolates with non-susceptibility to itraconazole, and high MICs of voriconazole and isavuconazole, harboured G138C, previously associated with azole-resistant A. fumigatus Some novel mutations were only identified amongst isolates with high azole MICs. However, cyp51A homology modelling did not cause a significant protein structure change for these mutations. There was no correlation between extrolite patterns and susceptibility. For A. viridinutans complex isolates, cyp51A mutations and the extrolites they produced were not major causes of antifungal resistance. Luliconazole and olorofim show promise for treating azole-resistant infections caused by these cryptic species.
Original languageEnglish
Article numbere00632-19
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number11
Number of pages13
ISSN0066-4804
DOIs
Publication statusPublished - 2019

Keywords

  • Cryptic species
  • Aspergillus viridinutans
  • Aspergillus felis
  • Aspergillus udagawae
  • Azole resistance
  • cyp51A

Cite this

Talbot, Jessica J. ; Frisvad, Jens Christian ; Meis, Jacques F. ; Hagen, Ferry ; Verweij, Paul E. ; Hibbs, David E. ; Lai, Felcia ; Samson, Robert A. ; Kidd, Sarah E. ; Barrs, Vanessa R. ; Houbraken, Jos. / Cyp51A mutations, Extrolite Profiles and Antifungal Susceptibility in Clinical and Environmental Isolates of the Aspergillus viridinutans Species Complex. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 11.
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title = "Cyp51A mutations, Extrolite Profiles and Antifungal Susceptibility in Clinical and Environmental Isolates of the Aspergillus viridinutans Species Complex",
abstract = "The past decade has seen an increase in aspergillosis in humans and animals due to Aspergillus viridinutans species complex members. Azole resistance is common to these infections, carrying a poor prognosis. Cyp51A gene mutations are the main cause of acquired azole resistance in Aspergillus fumigatus This study aimed to determine if azole-resistant phenotype in A. viridinutans complex members is associated with cyp51A mutations or extrolite profiles. The cyp51A gene of clinical and environmental isolates was amplified using novel primers, antifungal susceptibility was tested using Clinical Laboratory Standards Institute methodology and extrolite profiling was performed using agar plug extraction. Very high azole minimum inhibitory concentrations (MICs) were detected in 84{\%} of the isolates (31/37). MICs of newer antifungals luliconazole and olorofim (F901318) were low for all isolates. Cyp51A sequences revealed 113 non-synonymous mutations compared to wild-type A. fumigatus M172A/V and D255G, previously associated with A. fumigatus azole resistance, were common amongst all isolates but were not correlated with azole MICs. Two environmental isolates with non-susceptibility to itraconazole, and high MICs of voriconazole and isavuconazole, harboured G138C, previously associated with azole-resistant A. fumigatus Some novel mutations were only identified amongst isolates with high azole MICs. However, cyp51A homology modelling did not cause a significant protein structure change for these mutations. There was no correlation between extrolite patterns and susceptibility. For A. viridinutans complex isolates, cyp51A mutations and the extrolites they produced were not major causes of antifungal resistance. Luliconazole and olorofim show promise for treating azole-resistant infections caused by these cryptic species.",
keywords = "Cryptic species, Aspergillus viridinutans, Aspergillus felis, Aspergillus udagawae, Azole resistance, cyp51A",
author = "Talbot, {Jessica J.} and Frisvad, {Jens Christian} and Meis, {Jacques F.} and Ferry Hagen and Verweij, {Paul E.} and Hibbs, {David E.} and Felcia Lai and Samson, {Robert A.} and Kidd, {Sarah E.} and Barrs, {Vanessa R.} and Jos Houbraken",
year = "2019",
doi = "10.1128/AAC.00632-19",
language = "English",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
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Cyp51A mutations, Extrolite Profiles and Antifungal Susceptibility in Clinical and Environmental Isolates of the Aspergillus viridinutans Species Complex. / Talbot, Jessica J.; Frisvad, Jens Christian; Meis, Jacques F.; Hagen, Ferry; Verweij, Paul E.; Hibbs, David E.; Lai, Felcia; Samson, Robert A.; Kidd, Sarah E.; Barrs, Vanessa R.; Houbraken, Jos.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 11, e00632-19, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Cyp51A mutations, Extrolite Profiles and Antifungal Susceptibility in Clinical and Environmental Isolates of the Aspergillus viridinutans Species Complex

AU - Talbot, Jessica J.

AU - Frisvad, Jens Christian

AU - Meis, Jacques F.

AU - Hagen, Ferry

AU - Verweij, Paul E.

AU - Hibbs, David E.

AU - Lai, Felcia

AU - Samson, Robert A.

AU - Kidd, Sarah E.

AU - Barrs, Vanessa R.

AU - Houbraken, Jos

PY - 2019

Y1 - 2019

N2 - The past decade has seen an increase in aspergillosis in humans and animals due to Aspergillus viridinutans species complex members. Azole resistance is common to these infections, carrying a poor prognosis. Cyp51A gene mutations are the main cause of acquired azole resistance in Aspergillus fumigatus This study aimed to determine if azole-resistant phenotype in A. viridinutans complex members is associated with cyp51A mutations or extrolite profiles. The cyp51A gene of clinical and environmental isolates was amplified using novel primers, antifungal susceptibility was tested using Clinical Laboratory Standards Institute methodology and extrolite profiling was performed using agar plug extraction. Very high azole minimum inhibitory concentrations (MICs) were detected in 84% of the isolates (31/37). MICs of newer antifungals luliconazole and olorofim (F901318) were low for all isolates. Cyp51A sequences revealed 113 non-synonymous mutations compared to wild-type A. fumigatus M172A/V and D255G, previously associated with A. fumigatus azole resistance, were common amongst all isolates but were not correlated with azole MICs. Two environmental isolates with non-susceptibility to itraconazole, and high MICs of voriconazole and isavuconazole, harboured G138C, previously associated with azole-resistant A. fumigatus Some novel mutations were only identified amongst isolates with high azole MICs. However, cyp51A homology modelling did not cause a significant protein structure change for these mutations. There was no correlation between extrolite patterns and susceptibility. For A. viridinutans complex isolates, cyp51A mutations and the extrolites they produced were not major causes of antifungal resistance. Luliconazole and olorofim show promise for treating azole-resistant infections caused by these cryptic species.

AB - The past decade has seen an increase in aspergillosis in humans and animals due to Aspergillus viridinutans species complex members. Azole resistance is common to these infections, carrying a poor prognosis. Cyp51A gene mutations are the main cause of acquired azole resistance in Aspergillus fumigatus This study aimed to determine if azole-resistant phenotype in A. viridinutans complex members is associated with cyp51A mutations or extrolite profiles. The cyp51A gene of clinical and environmental isolates was amplified using novel primers, antifungal susceptibility was tested using Clinical Laboratory Standards Institute methodology and extrolite profiling was performed using agar plug extraction. Very high azole minimum inhibitory concentrations (MICs) were detected in 84% of the isolates (31/37). MICs of newer antifungals luliconazole and olorofim (F901318) were low for all isolates. Cyp51A sequences revealed 113 non-synonymous mutations compared to wild-type A. fumigatus M172A/V and D255G, previously associated with A. fumigatus azole resistance, were common amongst all isolates but were not correlated with azole MICs. Two environmental isolates with non-susceptibility to itraconazole, and high MICs of voriconazole and isavuconazole, harboured G138C, previously associated with azole-resistant A. fumigatus Some novel mutations were only identified amongst isolates with high azole MICs. However, cyp51A homology modelling did not cause a significant protein structure change for these mutations. There was no correlation between extrolite patterns and susceptibility. For A. viridinutans complex isolates, cyp51A mutations and the extrolites they produced were not major causes of antifungal resistance. Luliconazole and olorofim show promise for treating azole-resistant infections caused by these cryptic species.

KW - Cryptic species

KW - Aspergillus viridinutans

KW - Aspergillus felis

KW - Aspergillus udagawae

KW - Azole resistance

KW - cyp51A

U2 - 10.1128/AAC.00632-19

DO - 10.1128/AAC.00632-19

M3 - Journal article

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 11

M1 - e00632-19

ER -