Comparative Genomics of Serial Candida glabrata Isolates and the Rapid Acquisition of Echinocandin Resistance during Therapy

Abstract

The opportunistic pathogen Candida glabrata shows a concerning increase in drug resistance. Here, we present the analysis of two serial bloodstream isolates, obtained 12 days apart. Both isolates show pan-azole resistance and echinocandin resistance was acquired during the sampling interval. Genome sequencing identified nine nonsynonymous SNVs between the strains, including a S663P substitution in FKS2 and previously undescribed SNVs in MDE1 and FPR1, offering insight into how C. glabrata acquires drug resistance and adapts to a human host.

Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations

“…Additionally, it is known that FKS1 and FKS2 mutations can confer resistance to echinocandin drugs in C. glabrata (Katiyar et al, 2012; Arendrup and Perlin, 2014). Consistent with previous studies (Barber et al, 2018), the second isolate of the pair NRZ-2016-057/NRZ-2016-058 presented a non-synonymous mutation in FKS2 (S663P), which correlated with the acquisition of echinocandin resistance. The original comparison of the two echinocandin resistant strains, CMRL2 and CMRL4, with their susceptible paired strains, reported mutations in FKS1 (S629P) and FKS2 (S663P), respectively (Biswas et al, 2017).…”

“…In addition, five other pairs of isolates (DSY562/DSY565, NRZ-2016-057/NRZ-2016-058, CMRL1/CMRL2, CMRL3/CMRL4, and CMRL5/CMRL6) included in this study, have been shown to present different resistance profiles to antifungal drugs (Supplementary Table S5). DSY565, CMRL6, NRZ-2016-057, and NRZ-2016-058 were shown to be azole resistant; and CMRL2, CMRL4, and NRZ-2016-058 were shown to be echinocandin resistant (Biswas et al, 2017; Vale-Silva et al, 2017; Barber et al, 2018).…”

“…To obtain an overall view of the genomic variation of C. glabrata in patients under treatment, we re-analyzed different samples from previous studies (Håvelsrud and Gaustad, 2017; Vale-Silva et al, 2017; Barber et al, 2018; Carreté et al, 2018). In addition we sequenced a trio of serial isolates.…”

“…Although such studies show evidence for relatively recent recombination (i.e., unique to one or few isolates within a clade), it is unknown whether this recombination can occur in the course of human infection or commensalism. Several recent studies have compared genome sequences from C. glabrata isolates obtained from the same patient (Singh-Babak et al, 2012; Biswas et al, 2017; Håvelsrud and Gaustad, 2017; Vale-Silva et al, 2017; Barber et al, 2018; Carreté et al, 2018). Most of these analyses revealed very little genetic variation, supporting the idea that a single clonal population colonizes different body sites and jointly contributes to infection.…”

A non-canonical DNA damage checkpoint response in a major fungal pathogen

“…Unlike S. cerevisiae , however, C. glabrata is an obligate human commensal microbe that can become pathogenic and is a leading cause of life-threatening invasive fungal infections in immunocompromised individuals 13–15 . C. glabrata rapidly develops resistance to different antifungal drug classes 12,16–20 and is characterized by extremely high genome variation among clinical isolates both in terms of single nucleotide polymorphisms and larger structural variants 9–12,21 . The documented extensive chromosomal variation among C. glabrata clinical isolates resembles the unstable karyotypes and increased gross chromosomal rearrangements observed in S. cerevisiae mutants lacking DNA replication checkpoint functions 22,23 .…”