Oct 16, 2019

Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species

Antimicrobial Agents and Chemotherapy
Mili KapoorKaren J Shaw

Abstract

Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for the treatment of invasive fungal infections. We determined that the median frequencies of spontaneous mutations conferring reduced susceptibility to MGX in Candida albicans, C. glabrata, and C. parapsilosis ranged from 3 × 10-8 to <1.85 × 10-8 Serial passage on agar identified mutants of C. albicans and C. parapsilosis with reduced susceptibility to MGX; however, this methodology did not result in C. glabrata mutants with reduced susceptibility. Similarly, serial passage in broth resulted in ≤2-fold changes in population MIC values for C. tropicalis, C. auris, and C. glabrata A spontaneous V163A mutation in the Gwt1 protein of C. glabrata and a corresponding C. albicans heterozygous V162A mutant were obtained. A C. glabrata V163A Gwt1 mutant generated using CRISPR, along with V162A and V168A mutants expressed in C. albicans and Saccharomyces cerevisiae Gwt1, respectively, all demonstrated reduced susceptibility to MGX versus control strains, suggesting the importance of this valine residue to MGX binding acros...Continue Reading

  • References33
  • Citations2

References

  • References33
  • Citations2

Citations

Mentioned in this Paper

Protein Biosynthesis Pathway
Candida albicans
CRISPR-Cas Systems
Antibiotics, Antifungal
Inhibitors
Invasive Mycosis
Evaluation
Candida glabrata
Caspofungin
Disease Susceptibility

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