Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]

Publication Date:
2018-05-26
Publisher:
The American Society for Microbiology (ASM)
Print ISSN:
0066-4804
Electronic ISSN:
1098-6596
Topics:
Biology
Medicine
Published by:
http://www.asm.org/
_version_ 1836398944201998336
autor Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
beschreibung Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages.
citation_standardnr 6267464
datenlieferant ipn_articles
feed_id 515
feed_publisher The American Society for Microbiology (ASM)
feed_publisher_url http://www.asm.org/
insertion_date 2018-05-26
journaleissn 1098-6596
journalissn 0066-4804
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Microbiology (ASM)
quelle Antimicrobial Agents and Chemotherapy
relation http://aac.asm.org/cgi/content/short/62/6/e00241-18?rss=1
search_space articles
shingle_author_1 Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
shingle_author_2 Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
shingle_author_3 Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
shingle_author_4 Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
shingle_catch_all_1 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages.
Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_2 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages.
Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_3 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages.
Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_4 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages.
Garcia-Rubio, R., Alcazar-Fuoli, L., Monteiro, M. C., Monzon, S., Cuesta, I., Pelaez, T., Mellado, E.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_title_1 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
shingle_title_2 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
shingle_title_3 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
shingle_title_4 Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
timestamp 2025-06-30T23:35:07.282Z
titel Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
titel_suche Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms [Mechanisms of Resistance]
topic W
WW-YZ
uid ipn_articles_6267464