Caspofungin resistance in Candia auris due to mutations in Fks 1 with adjunctive role of chitin and key cell wall stress response pathway genes

The emergence of echinocandin resistance in has become a major concern. Point mutations in Fks1 subunit of β-D-glucan synthase is the primary mechanism in echinocandin resistance. However, resistant isolates with wild type 1 are not infrequent. We screened 199 clinical isolates from 30 centres across India for echinocandin resistance. The cohort also contained six sequential isolates from a liver transplant recipient. Eleven isolates (5.7%) from 11 patients, and those six serial isolates had elevated echinocandin minimum inhibitory concentrations (MIC). Three of these 17 isolates carried S639F mutation in hot spot 1 region of . A novel 1 mutation, F635Y was identified in two resistant isolates, and a related F635L mutation was detected in four of the six sequential isolates. Resistant isolates (MIC≥2 mg/L) and those with intermediate caspofungin susceptibility (MIC, 1.0 mg/L) demonstrated higher induction of chitin synthase gene, 1 [resistant, 2.2(1.3-5.8); intermediate, 6(2.5-11.2)] compared to susceptible isolates [1.2(0.8-2), P<0.05]. However, the expression of the subunit of β-1, 3-glucan synthase was higher only in intermediate group [3.4(2-8.5), P<0.01]. 1 MAP kinase showed higher inducible expression in intermediate isolates, while those of 90-like protein and B were comparable in resistant and intermediate groups. In one isolate pan-echinocandin resistance mediated by S639F mutation coupled with high basal chitin content was noted. This study reports novel mutation F635Y/L in in , contributing to echinocandin resistance and suggests the possible adjunctive roles of chitin synthase, , and cell wall-remodeling pathway gene upregulation in caspofungin resistance.