title: Epidemiological and Genomic Landscape of Azole Resistance Mechanisms inAspergillusFungi.
abstract: Invasive aspergillosis is a life-threatening mycosis caused by the pathogenic fungusAspergillus. The predominant causal species isAspergillus fumigatus, and azole drugs are the treatment of choice. Azole drugs approved for clinical use include itraconazole, voriconazole, posaconazole, and the recently added isavuconazole. However, epidemiological research has indicated that the prevalence of azole-resistantA. fumigatusisolates has increased significantly over the last decade. What is worse is that azole-resistant strains are likely to have emerged not only in response to long-term drug treatment but also because of exposure to azole fungicides in the environment. Resistance mechanisms include amino acid substitutions in the target Cyp51A protein, tandem repeat sequence insertions at thecyp51Apromoter, and overexpression of the ABC transporter Cdr1B. Environmental azole-resistant strains harboring the association of a tandem repeat sequence and punctual mutation of the Cyp51A gene (TR34/L98H and TR46/Y121F/T289A) have become widely disseminated across the world within a short time period. The epidemiological data also suggests that the number ofAspergillusspp. other thanA. fumigatusisolated has risen. Some non-fumigatusspecies intrinsically show low susceptibility to azole drugs, imposing the need for accurate identification, and drug susceptibility testing in most clinical cases. Currently, our knowledge of azole resistance mechanisms in non-fumigatus Aspergillusspecies such asA. flavus, A. niger, A. tubingensis, A. terreus, A. fischeri, A. lentulus, A. udagawae, andA. calidoustusis limited. In this review, we present recent advances in our understanding of azole resistance mechanisms particularly inA. fumigatus. We then provide an overview of the genome sequences of non-fumigatusspecies, focusing on the proteins related to azole resistance mechanisms.
authors.affiliation: Medical Mycology Research Center, Chiba University Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hagiwara
authors.affiliation: Medical Mycology Research Center, Chiba University Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Medical Mycology Research Center, Chiba University Chiba, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Ribeirão Preto, Brazil.
authors.forename: Gustavo H
authors.initials: GH
authors.lastname: Goldman
keywords: A. flavus; A. niger; Aspergillus fumigatus; Aspergillus section Fumigati; Cdr1B; Cyp51A; azole resistance; tandem repeats