Isavuconazole nonwildtype Aspergillus fumigatus isolates from a global surveillance study display alterations in multiple genes involved in the ergosterol biosynthesis pathway not previously associated with resistance to other azoles

Autor:	Lalitagauri M. Deshpande, Andrew P. Davis, Timothy D Collingsworth, Mariana Castanheira, Michael A. Pfaller
Rok vydání:	2021
Předmět:	Azoles 0301 basic medicine Antifungal Agents Pyridines Itraconazole 030106 microbiology Microbial Sensitivity Tests Dermatology Aspergillus fumigatus Frameshift mutation Microbiology Fungal Proteins 030207 dermatology & venereal diseases 03 medical and health sciences 0302 clinical medicine Drug Resistance Fungal Ergosterol Nitriles medicine Humans Gene chemistry.chemical_classification Voriconazole Whole genome sequencing Whole Genome Sequencing biology Broth microdilution General Medicine Triazoles biology.organism_classification Infectious Diseases chemistry Azole medicine.drug
Zdroj:	Mycoses. 64:1279-1290
ISSN:	1439-0507 0933-7407
Popis:	OBJECTIVES We evaluated 35 azole nonwildtype Aspergillus fumigatus isolates that were collected during 2017-2018 using whole genome sequencing (WGS) to detect alterations in the genes involved in the ergosterol biosynthesis pathway as well as other genes associated with azole resistance. METHODS Among 297 A fumigatus isolates collected worldwide, 36 isolates displayed nonwildtype MIC values to isavuconazole, itraconazole, or voriconazole when tested by the CLSI reference broth microdilution method. Isolates were submitted to WGS and results were compared to 2 azolewildtype isolates. RESULTS Among the 35 sequenced isolates (1 failed to produce quality sequences), 29 were nonwildtype to isavuconazole, 16 were nonwildtype to itraconazole, and 9 were nonwildtype to voriconazole (CLSI M59Ed2 criteria). A total of 9 isolates carried Cyp51A TR34/L98H alterations (8 from Italy and 1 from Belgium) and had nonwildtype MIC values for ≥2 azoles. A Cyp51B Q42L mutation was detected in 3 isolates, 1 nonwildtype voriconazole and 2 nonwildtype isavuconazole isolates. Three isolates harboured multiple mutations in Cyp51A (F46Y, M172V, E427K ± N248T, and D255E), including 1 isolate with the Cyp51B Q42L mutation. Mutations causing frameshifts, early termination, and duplications were observed among several genes and were more prevalent in isavuconazole nonwildtype isolates (66.7%) than in the isolates that were nonwildtype to 1 or 2 other azoles (22.2%). Nine isolates harboured frameshift mutations in a ERG25 homologue that is usually associated with changes in other genes and should be further evaluated. CONCLUSIONS Cyp51A L98H/TR34 was the most common alteration observed among the azole nonwildtype A fumigatus isolates from a large surveillance study; however, only isolates that were nonwildtype to isavuconazole had alterations in multiple analysed genes. These isolates deserve further evaluation.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f3de5b9c9a9e4a1f3049f7719182f59 https://doi.org/10.1111/myc.13267 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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