Dataset Information

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

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 across different species. Cross-resistance to the three major classes of antifungals was evaluated, but no changes in susceptibility to amphotericin B or caspofungin were observed in any mutant. No change was observed in fluconazole susceptibility, with the exception of a single non-Gwt1 mutant, where a 4-fold increase in the fluconazole MIC was observed. MGX demonstrated a relatively low potential for resistance development, consistent with other approved antifungal agents and those in clinical development.

SUBMITTER: Kapoor M

PROVIDER: S-EPMC7187586 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Kapoor Mili M Moloney Molly M Soltow Quinlyn A QA Pillar Chris M CM Shaw Karen Joy KJ

Antimicrobial agents and chemotherapy 20191220 1

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 ...[more]

PMID: 31611349

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Project description:Manogepix (APX001A) is the active moiety of the drug candidate fosmanogepix (APX001), currently in clinical development for the treatment of invasive fungal infections. We compared manogepix EUCAST minimum effective concentrations (MECs) to MICs of five comparators and CLSI MECs and MICs by a colorimetric method against contemporary molds. EUCAST susceptibility testing was performed for 161 isolates. Interlaboratory and intermethod reproducibility were determined by comparison with published manogepix MECs. Colorimetric MICs (measuring metabolic activity) were evaluated using three Aspergillus fumigatus isolates and one Aspergillus flavus isolate with four inocula at 24 to 48 h of incubation and 1 to 3 h 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT)/menadione (MEN) exposure. Manogepix modal MECs (range in mg/liter) against Aspergillus species were 0.03 to 0.06 (0.008 to 0.125) and unaffected by itraconazole resistance. Manogepix was as active against two Fusarium isolates but inactive against Trichophyton interdigitale, Lichtheimia ramosa, and Rhizomucor pusillus isolates (MECs >0.5). Modal MEC/MICs were ≥3 2-fold dilutions apart without overlapping ranges comparing manogepix with amphotericin B, isavuconazole, and voriconazole against Aspergillus isolates. Manogepix and posaconazole MECs/MICs correlated for Aspergillus niger (Pearson's r = 0.711; P = 0.0044). The MEC at which 50% of the isolates tested are inhibited (MEC50), mode, and MEC90 values were within ±1 dilution in all cases compared with published EUCAST and CLSI data. The colorimetric method showed excellent agreement with the MECs when plates were inoculated with the lowest inoculum (1 × 102 CFU/ml to 2.5 × 102 CFU/ml), incubated for 24 h, and exposed for 1 to 3 h to XTT/MEN. Broad-spectrum in vitro activity of manogepix against clinically relevant molds was confirmed with excellent agreement across EUCAST and CLSI methods reported from experienced mycology laboratories. Colorimetric MIC determination warrants further investigation as a potential alternative that is less dependent on mycology expertise.

Project description:Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC50, 0.008 μg/ml; MIC90, 0.06 μg/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC50], 0.015 μg/ml; MEC90, 0.03 μg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 μg/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

Dataset Information

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

Publications

Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in <i>Candida</i> Species.

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