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Open AccessArticle

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

1
Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain
2
Spanish Network for Research in Infectious Diseases (REIPI RD16/CIII/0004/0003), ISCIII, Majadahonda, 28220 Madrid, Spain
3
Hospital Universitario Central de Asturias, Fundación para la Investigación Biosanitaria del Principado de Asturias (FINBA), Oviedo, 33011 Asturias, Spain
*
Author to whom correspondence should be addressed.
Genes 2020, 11(10), 1217; https://doi.org/10.3390/genes11101217
Received: 9 July 2020 / Revised: 8 October 2020 / Accepted: 13 October 2020 / Published: 17 October 2020
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. View Full-Text
Keywords: Aspergillus flavus; Cyp51s; azole resistance mechanisms; azole drugs; DMIs fungicides Aspergillus flavus; Cyp51s; azole resistance mechanisms; azole drugs; DMIs fungicides
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Lucio, J.; Gonzalez-Jimenez, I.; Rivero-Menendez, O.; Alastruey-Izquierdo, A.; Pelaez, T.; Alcazar-Fuoli, L.; Mellado, E. Point Mutations in the 14-α Sterol Demethylase Cyp51A or Cyp51C Could Contribute to Azole Resistance in Aspergillus flavus. Genes 2020, 11, 1217.

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