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Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates

Objectives: Azole-resistant Candida tropicalis has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in C. tropicalis have focused on the difference of genotypes and molecular mechanisms b...

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Autores principales: Chen, Pao-Yu, Chuang, Yu-Chung, Wu, Un-In, Sun, Hsin-Yun, Wang, Jann-Tay, Sheng, Wang-Huei, Chen, Yee-Chun, Chang, Shan-Chwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396981/
https://www.ncbi.nlm.nih.gov/pubmed/34436151
http://dx.doi.org/10.3390/jof7080612
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author Chen, Pao-Yu
Chuang, Yu-Chung
Wu, Un-In
Sun, Hsin-Yun
Wang, Jann-Tay
Sheng, Wang-Huei
Chen, Yee-Chun
Chang, Shan-Chwen
author_facet Chen, Pao-Yu
Chuang, Yu-Chung
Wu, Un-In
Sun, Hsin-Yun
Wang, Jann-Tay
Sheng, Wang-Huei
Chen, Yee-Chun
Chang, Shan-Chwen
author_sort Chen, Pao-Yu
collection PubMed
description Objectives: Azole-resistant Candida tropicalis has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in C. tropicalis have focused on the difference of genotypes and molecular mechanisms between these two traits. Methods: Sixty-four non-duplicated C. tropicalis bloodstream isolates collected in 2017 were evaluated for azole MICs by the EUCAST E.def 7.3.1 method, diploid sequence type (DST) by multilocus sequencing typing, and sequences and expression levels of genes encoding ERG11, its transcription factor, UPC2, and efflux pumps (CDR1, CDR2 and MDR1). Results: Isavuconazole showed the highest in vitro activity and trailing against C. tropicalis, followed by voriconazole and fluconazole (geometric mean [GM] MIC, 0.008, 0.090, 1.163 mg/L, respectively; trailing GM, 27.4%, 20.8% and 19.5%, respectively; both overall p < 0.001). Fourteen (21.9%) isolates were non-WT to fluconazole/voriconazole, 12 of which were non-WT to isavuconazole and clustered in clonal complex (CC) 3. Twenty-five (39.1%) isolates were high trailing WT, including all CC2 isolates (44.0%) (containing DST140 and DST98). All azole non-WT isolates carried the ERG11 mutations A395T/W and/or C461T/Y, and most carried the UPC2 mutation T503C/Y. These mutations were not identified in low and high trailing WT isolates. Azole non-WT and high trailing WT isolates exhibited the highest expression levels of ERG11 and MDR1, 3.91- and 2.30-fold, respectively (both overall p < 0.01). Conclusions: Azole resistance and trailing are phenotypically and genotypically different in C. tropicalis. Interference with azole binding and MDR1 up-regulation confer azole resistance and trailing, respectively.
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spelling pubmed-83969812021-08-28 Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates Chen, Pao-Yu Chuang, Yu-Chung Wu, Un-In Sun, Hsin-Yun Wang, Jann-Tay Sheng, Wang-Huei Chen, Yee-Chun Chang, Shan-Chwen J Fungi (Basel) Article Objectives: Azole-resistant Candida tropicalis has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in C. tropicalis have focused on the difference of genotypes and molecular mechanisms between these two traits. Methods: Sixty-four non-duplicated C. tropicalis bloodstream isolates collected in 2017 were evaluated for azole MICs by the EUCAST E.def 7.3.1 method, diploid sequence type (DST) by multilocus sequencing typing, and sequences and expression levels of genes encoding ERG11, its transcription factor, UPC2, and efflux pumps (CDR1, CDR2 and MDR1). Results: Isavuconazole showed the highest in vitro activity and trailing against C. tropicalis, followed by voriconazole and fluconazole (geometric mean [GM] MIC, 0.008, 0.090, 1.163 mg/L, respectively; trailing GM, 27.4%, 20.8% and 19.5%, respectively; both overall p < 0.001). Fourteen (21.9%) isolates were non-WT to fluconazole/voriconazole, 12 of which were non-WT to isavuconazole and clustered in clonal complex (CC) 3. Twenty-five (39.1%) isolates were high trailing WT, including all CC2 isolates (44.0%) (containing DST140 and DST98). All azole non-WT isolates carried the ERG11 mutations A395T/W and/or C461T/Y, and most carried the UPC2 mutation T503C/Y. These mutations were not identified in low and high trailing WT isolates. Azole non-WT and high trailing WT isolates exhibited the highest expression levels of ERG11 and MDR1, 3.91- and 2.30-fold, respectively (both overall p < 0.01). Conclusions: Azole resistance and trailing are phenotypically and genotypically different in C. tropicalis. Interference with azole binding and MDR1 up-regulation confer azole resistance and trailing, respectively. MDPI 2021-07-28 /pmc/articles/PMC8396981/ /pubmed/34436151 http://dx.doi.org/10.3390/jof7080612 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Pao-Yu
Chuang, Yu-Chung
Wu, Un-In
Sun, Hsin-Yun
Wang, Jann-Tay
Sheng, Wang-Huei
Chen, Yee-Chun
Chang, Shan-Chwen
Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title_full Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title_fullStr Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title_full_unstemmed Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title_short Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates
title_sort mechanisms of azole resistance and trailing in candida tropicalis bloodstream isolates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396981/
https://www.ncbi.nlm.nih.gov/pubmed/34436151
http://dx.doi.org/10.3390/jof7080612
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