TY - JOUR
T1 - hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
AU - Souza, Ana C.O.
AU - Ge, Wenbo
AU - Wiederhold, Nathan P.
AU - Rybak, Jeffrey M.
AU - Fortwendel, Jarrod R.
AU - David Rogers, P.
N1 - Funding Information:
This work was supported by NIH grant R01 AI143197 to P.D.R. and J.R.F. A.C.O.S. performed experiments, interpreted results, and wrote the manuscript. W.G. performed experiments. N.P.W. provided critical input and feedback. J.M.R. interpreted results, provided critical feedback, and assisted in writing the manuscript. J.R.F. and P.D.R. interpreted results, provided critical feedback, assisted in writing the manuscript, and supervised the study.
Publisher Copyright:
Copyright © 2023 Souza et a.
PY - 2023/5
Y1 - 2023/5
N2 - Aspergillus fumigatus is a ubiquitous environmental mold that can cause severe disease in immunocompromised patients and chronic disease in individuals with underlying lung conditions. Triazoles are the most widely used class of antifungal drugs to treat A. fumigatus infections, but their use in the clinic is threatened by the emergence of triazole-resistant isolates worldwide, reinforcing the need for a better understanding of resistance mechanisms. The predominant mechanisms of A. fumigatus triazole resistance involve mutations affecting the promoter region or coding sequence of the target enzyme of the triazoles, Cyp51A. However, triazole-resistant isolates without cyp51A-associated mutations are frequently identified. In this study, we investigate a pan-triazole-resistant clinical isolate, DI15-105, that simultaneously carries the mutations hapEP88L and hmg1F262del, with no mutations in cyp51A. Using a Cas9-mediated gene-editing system, hapEP88L and hmg1F262del mutations were reverted in DI15-105. Here, we show that the combination of these mutations accounts for pan-triazole resistance in DI15-105. To our knowledge, DI15-105 is the first clinical isolate reported to simultaneously carry mutations in hapE and hmg1 and only the second with the hapEP88L mutation. IMPORTANCE Triazole resistance is an important cause of treatment failure and high mortality rates for A. fumigatus human infections. Although Cyp51A-associated mutations are frequently identified as the cause of A. fumigatus triazole resistance, they do not explain the resistance phenotypes for several isolates. In this study, we demonstrate that hapE and hmg1 mutations additively contribute to pan-triazole resistance in an A. fumigatus clinical isolate lacking cyp51-associated mutations. Our results exemplify the importance of and the need for a better understanding of cyp51A-independent triazole resistance mechanisms.
AB - Aspergillus fumigatus is a ubiquitous environmental mold that can cause severe disease in immunocompromised patients and chronic disease in individuals with underlying lung conditions. Triazoles are the most widely used class of antifungal drugs to treat A. fumigatus infections, but their use in the clinic is threatened by the emergence of triazole-resistant isolates worldwide, reinforcing the need for a better understanding of resistance mechanisms. The predominant mechanisms of A. fumigatus triazole resistance involve mutations affecting the promoter region or coding sequence of the target enzyme of the triazoles, Cyp51A. However, triazole-resistant isolates without cyp51A-associated mutations are frequently identified. In this study, we investigate a pan-triazole-resistant clinical isolate, DI15-105, that simultaneously carries the mutations hapEP88L and hmg1F262del, with no mutations in cyp51A. Using a Cas9-mediated gene-editing system, hapEP88L and hmg1F262del mutations were reverted in DI15-105. Here, we show that the combination of these mutations accounts for pan-triazole resistance in DI15-105. To our knowledge, DI15-105 is the first clinical isolate reported to simultaneously carry mutations in hapE and hmg1 and only the second with the hapEP88L mutation. IMPORTANCE Triazole resistance is an important cause of treatment failure and high mortality rates for A. fumigatus human infections. Although Cyp51A-associated mutations are frequently identified as the cause of A. fumigatus triazole resistance, they do not explain the resistance phenotypes for several isolates. In this study, we demonstrate that hapE and hmg1 mutations additively contribute to pan-triazole resistance in an A. fumigatus clinical isolate lacking cyp51-associated mutations. Our results exemplify the importance of and the need for a better understanding of cyp51A-independent triazole resistance mechanisms.
KW - CCAAT box binding complex
KW - hapE
KW - hmg1
KW - KEYWORDS Aspergillus fumigatus
KW - triazole drug resistance
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UR - http://www.scopus.com/inward/citedby.url?scp=85163914259&partnerID=8YFLogxK
U2 - 10.1128/spectrum.05188-22
DO - 10.1128/spectrum.05188-22
M3 - Article
C2 - 37140376
AN - SCOPUS:85163914259
SN - 2165-0497
VL - 11
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 3
ER -