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

Evaluation of Resistance Development to the Gwt1 inhibitor Manogepix (APX001A) in Candida Species. Antimicrob Agents Chemother. 2019 Oct 14;: Authors: Kapoor M, Moloney M, Soltow QA, Pillar CM, Shaw KJ Abstract Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for 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 x 10-8 to <1.85 x 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, V168A mutants expressed in C. albicans and Saccharomyces cerevisiae Gwt1 respectively, all demonstrated reduced susceptibility to MGX vs control strains, suggesting the importance of this valine residue to MGX binding across different spe...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research