Echinocandin resistance in poses a serious clinical challenge. The underlying resistance mechanism of a pan-echinocandin-resistant isolate (strain L74) was investigated in this study. 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 /Fks2-E655K). Sequence analysis of strain L74 revealed a premature stop codon W508stop in and an E655K mutation preceding the hotspot 1 region in . Introduction of the Fks2-E655K mutation in ATCC 2001 (strain CRISPR 31) conferred a modest reduction in susceptibility. However, the same mutation in the background (strain /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 transcript ratios and Fks1/Fks2 protein ratios were significantly lower in L74 and /Fks2-E655K compared to ATCC 2001 and CRISPR 31 ( <0.05). Mice challenged with CRISPR 31 and /Fks2-E655K mutants failed to respond to MCF. In conclusion, the high-level of echinocandin resistance in the clinical isolate of L74 was concluded to result from the combination of null function of Fks1 and the point mutation E655K in Fks2.
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| http://dx.doi.org/10.1080/22221751.2019.1684209 | DOI Listing |
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