De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance

Abstract

SCY-078 is an orally active antifungal whose target is the β-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC₅₀ (50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS.

Keywords: Candida glabrata; SCY-078; resistance.

FIG 1

Structures of SCY-078, a semisynthetic enfumafungin derivative, and micafungin, an echinocandin.

FIG 2

Antifungal inhibition profiles of enriched GS complexes from representative susceptible and SCY-078-resistant C. glabrata isolates for micafungin (MCF) and SCY-078.

FIG 3

Prediction model of C. glabrata Fks2 membrane protein topology (gray bars, transmembrane regions [TMH]; hot spot regions are marked with green circles). Note that amino acids in positions 715 and 1390 (marked with blue dots) are in TMHVI and TMHVIII, respectively. In silico TMH predictions were generated using TMHMM (http://www.cbs.dtu.dk/services/TMHMM) and PRO-TMHMM (http://topcons.cbr.su.se).