Abstract
Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole-resistant clinical Aspergillus fumigatus isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapEP88L mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the cyp51A gene, which encodes the target of azoles, the 14-α sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists cyp51A repression in low-iron environments and that this iron-dependent effect is lost in the HapEP88L mutant. Altogether, these results indicate that the mutation HapEP88L confers increased resistance to azoles compared with wt A. fumigatus, particularly in low-iron clinical niches such as the lung.
Highlights
The global burden of aspergillosis exceeds 14 million people and mortality rates are especially high in patients with chronic and invasive diseases (Bongomin et al, 2017)
Infections with azole-resistant A. fumigatus are of growing concern in clinics
Patients suffering from drug-resistant invasive aspergillosis face mortality rates of up to 100% (Meis et al, 2016)
Summary
The global burden of aspergillosis exceeds 14 million people and mortality rates are especially high in patients with chronic and invasive diseases (Bongomin et al, 2017). In some European centers, the levels of resistance exceed 20% and the U.S Centers for Disease Control and Prevention have placed Aspergillus fumigatus, the primary etiological agent responsible for aspergillosis, on their watch list for antibiotic-resistant pathogens (https:// www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threatsreport-508.pdf). This worldwide development is of growing concern and demands a thorough understanding of the molecular mechanisms that contribute to drug resistance to support the development of alternative therapeutic strategies. Depending on the target gene and other transcriptional regulators, the CBC hereby either activates or inhibits gene expression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
