A novel GWT1 A397T substitution combined with TAC1B F214I reduces manogepix susceptibility and fosmanogepix efficacy in Candida auris.

Authors

Tatsuro Hirayama, Natsume Kitahori, Mizuki Ishimine, NaNa Nakada, Yuya Ito, Naoki Iwanaga, Takahiro Takazono, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kazuhiro Tsukamoto, Hiroshi Mukae

Published in

Microbiology spectrum. Pages e0207826. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

Fosmanogepix (FMGX) is the prodrug of manogepix (MGX), which targets Gwt1, an inositol acyltransferase encoded by GWT1 and required for glycosylphosphatidylinositol anchor biosynthesis. To identify genetic changes associated with reduced MGX susceptibility in Candida auris, we exposed strain NCPF8971 to MGX. A stable isolate with an MGX minimum inhibitory concentration (MIC) of 1.0 µg/mL compared with 0.03 µg/mL for the parental strain carried GWT1 A397T and TAC1B F214I substitutions. Reciprocal CRISPR-Cas9 editing demonstrated that GWT1 A397T, TAC1B F214I, and the combined substitutions increased the MIC to 0.06, 0.5, and 1.0 µg/mL, respectively; reversion restored the MIC stepwise to the parental level. In a Galleria mellonella infection model, FMGX improved survival and reduced fungal burden in larvae infected with the parental strain, whereas these effects were attenuated or absent in larvae infected with the engineered mutants. These findings identify GWT1 A397T as a modest contributor to reduced MGX susceptibility and show that this target alteration further increases the MIC in a TAC1B F214I background. The combined genotype was associated with a diminished FMGX treatment response in this invertebrate model.IMPORTANCECandida auris is an emerging yeast that can resist several antifungal drugs and cause difficult-to-treat invasive infections. Fosmanogepix is an antifungal agent that acts on a target different from those of existing drugs. We investigated how C. auris could become less susceptible to fosmanogepix and whether the responsible genetic changes would affect treatment in an infection model. We found that a change in the protein targeted by the drug modestly reduced susceptibility, whereas a change in a regulatory protein previously linked to increased activity of a drug efflux pump caused a greater reduction; the combination of both changes further weakened the drug's activity. The combined changes were also associated with a reduced response to fosmanogepix in an insect infection model. These findings show that changes affecting the drug target and drug efflux may act together to reduce antifungal activity and support monitoring for multiple pathways of reduced susceptibility.

PMID:
42678188
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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