Novel FKS1 and FKS2 modifications in a high-level echinocandin resistant clinical isolate of Candida glabrata
| Autor: | Yan-Hai Zhang, Yong-Zhe Li, Xin Hou, He Wang, Padmaja Paderu, Kelley R. Healey, Meng Xiao, Yanan Zhao, Erika Shor, Milena Kordalewska, Li-Yan Lin, David S. Perlin, Ying Zhao, Yingchun Xu, Cristina Jiménez Ortigosa |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Antifungal Agents Echinocandin Epidemiology 030106 microbiology Immunology Candida glabrata Microbial Sensitivity Tests Microbiology Article Fungal Proteins 03 medical and health sciences Echinocandins Mice Drug Resistance Fungal Virology Drug Discovery polycyclic compounds medicine CRISPR Animals Humans FKS Mice Inbred BALB C Strain (chemistry) biology Candidiasis General Medicine biochemical phenomena metabolism and nutrition equipment and supplies biology.organism_classification bacterial infections and mycoses stomatognathic diseases 030104 developmental biology Infectious Diseases Glucosyltransferases Parasitology Female CRISPR-Cas9 echinocandin resistance medicine.drug resistance mechanism |
| Zdroj: | Emerging Microbes & Infections |
| ISSN: | 2222-1751 |
| Popis: | Echinocandin resistance in Candida glabrata poses a serious clinical challenge. The underlying resistance mechanism of a pan-echinocandin-resistant C. glabrata isolate (strain L74) was investigated in this study. FKS mutants carrying specific mutations found in L74 were reconstructed by the Alt-R CRISPR-Cas9 system (Fks1 WT/Fks2-E655K, strain CRISPR 31) and site-directed mutagenesis (strain fks1Δ/Fks2-E655K). Sequence analysis of strain L74 revealed a premature stop codon W508stop in FKS1 and an E655K mutation preceding the hotspot 1 region in FKS2. Introduction of the Fks2-E655K mutation in ATCC 2001 (strain CRISPR 31) conferred a modest reduction in susceptibility. However, the same FKS2 mutation in the fks1Δ background (strain fks1Δ/Fks2-E655K) resulted in high levels of resistance to echinocandins. Glucan synthase isolated from L74 was dramatically less sensitive to micafungin (MCF) relative to ATCC 2001. Both FKS1/FKS2 transcript ratios and Fks1/Fks2 protein ratios were significantly lower in L74 and fks1Δ/Fks2-E655K compared to ATCC 2001 and CRISPR 31 (P |
| Databáze: | OpenAIRE |
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