hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
ABSTRACT 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 u...
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| Materyal Türü: | Makale |
| Dil: | English |
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American Society for Microbiology
2023-06-01
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| Seri Bilgileri: | Microbiology Spectrum |
| Konular: | |
| Online Erişim: | https://journals.asm.org/doi/10.1128/spectrum.05188-22 |
| _version_ | 1827925094799769600 |
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| author | Ana C. O. Souza Wenbo Ge Nathan P. Wiederhold Jeffrey M. Rybak Jarrod R. Fortwendel P. David Rogers |
| author_facet | Ana C. O. Souza Wenbo Ge Nathan P. Wiederhold Jeffrey M. Rybak Jarrod R. Fortwendel P. David Rogers |
| author_sort | Ana C. O. Souza |
| collection | DOAJ |
| description | ABSTRACT 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. |
| first_indexed | 2024-03-13T05:20:15Z |
| format | Article |
| id | doaj.art-8a734e7ad5d14bd298a1db6bfd409309 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-13T05:20:15Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-8a734e7ad5d14bd298a1db6bfd4093092023-06-15T13:18:33ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.05188-22hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical IsolateAna C. O. Souza0Wenbo Ge1Nathan P. Wiederhold2Jeffrey M. Rybak3Jarrod R. Fortwendel4P. David Rogers5Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USAFungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USADepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USADepartment of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USADepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/spectrum.05188-22Aspergillus fumigatustriazole drug resistancehmg1hapECCAAT box binding complex |
| spellingShingle | Ana C. O. Souza Wenbo Ge Nathan P. Wiederhold Jeffrey M. Rybak Jarrod R. Fortwendel P. David Rogers hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate Microbiology Spectrum Aspergillus fumigatus triazole drug resistance hmg1 hapE CCAAT box binding complex |
| title | hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate |
| title_full | hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate |
| title_fullStr | hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate |
| title_full_unstemmed | hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate |
| title_short | hapE and hmg1 Mutations Are Drivers of cyp51A-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate |
| title_sort | hape and hmg1 mutations are drivers of cyp51a independent pan triazole resistance in an aspergillus fumigatus clinical isolate |
| topic | Aspergillus fumigatus triazole drug resistance hmg1 hapE CCAAT box binding complex |
| url | https://journals.asm.org/doi/10.1128/spectrum.05188-22 |
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