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

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,...

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Autores principales: Lucio, Jose, Gonzalez-Jimenez, Irene, Rivero-Menendez, Olga, Alastruey-Izquierdo, Ana, Pelaez, Teresa, Alcazar-Fuoli, Laura, Mellado, Emilia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602989/
https://www.ncbi.nlm.nih.gov/pubmed/33080784
http://dx.doi.org/10.3390/genes11101217
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author Lucio, Jose
Gonzalez-Jimenez, Irene
Rivero-Menendez, Olga
Alastruey-Izquierdo, Ana
Pelaez, Teresa
Alcazar-Fuoli, Laura
Mellado, Emilia
author_facet Lucio, Jose
Gonzalez-Jimenez, Irene
Rivero-Menendez, Olga
Alastruey-Izquierdo, Ana
Pelaez, Teresa
Alcazar-Fuoli, Laura
Mellado, Emilia
author_sort Lucio, Jose
collection PubMed
description 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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spelling pubmed-76029892020-11-01 Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus Lucio, Jose Gonzalez-Jimenez, Irene Rivero-Menendez, Olga Alastruey-Izquierdo, Ana Pelaez, Teresa Alcazar-Fuoli, Laura Mellado, Emilia Genes (Basel) Article 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. MDPI 2020-10-17 /pmc/articles/PMC7602989/ /pubmed/33080784 http://dx.doi.org/10.3390/genes11101217 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lucio, Jose
Gonzalez-Jimenez, Irene
Rivero-Menendez, Olga
Alastruey-Izquierdo, Ana
Pelaez, Teresa
Alcazar-Fuoli, Laura
Mellado, Emilia
Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title_full Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title_fullStr Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title_full_unstemmed Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title_short Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus
title_sort point mutations in the 14-α sterol demethylase cyp51a or cyp51c could contribute to azole resistance in aspergillus flavus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602989/
https://www.ncbi.nlm.nih.gov/pubmed/33080784
http://dx.doi.org/10.3390/genes11101217
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