ABSTRACT Manogepix, the active moiety of the prodrug fosmanogepix, is a novel investigational agent in clinical trials that inhibits Gwt1, depleting glycosylphosphatidylinositol (GPI)-anchored mannoproteins critical for fungal cell wall integrity. It has potent broad-spectrum antifungal activity, including against fungi that are often resistant to clinically available antifungals (e.g., Fusarium species and Lomentospora prolificans ). Our objective was to evaluate the in vitro activity of manogepix against different Aspergillus species, Coccidioides, and rare molds with reduced in vitro susceptibility or resistance to other antifungals. A total of 257 clinical isolates of Aspergillus, Coccidioides, Scopulariopsis/Microascus , Rasamsonia argillaceae species complex members, Purpureocillium lilacinum, Curvularia, Exophiala, and Exserohilum rostratum were used. Minimum effective concentrations (MECs) (manogepix and caspofungin) and minimum inhibitory concentrations (MICs) (amphotericin B, fluconazole, isavuconazole, itraconazole, posaconazole, and fluconazole) were determined by CLSI M38 broth dilution. Manogepix demonstrated potent in vitro activity against Aspergillus, Coccidioides, and several other molds (MEC range ≤ 0.002–0.015 mg/L; GM MEC range 0.003–0.007 mg/L). The activity of manogepix was also maintained against strains with reduced in vitro susceptibility to, or resistance to, other antifungals, including those with elevated MEC values to caspofungin, as well as isolates that were intrinsically resistant to other antifungals. Reduced or variable activity for manogepix was observed against Curvularia, Exophiala, and Exserohilum rostratum . Additional studies are warranted to determine if this potent in vitro activity translates into in vivo activity and enhanced clinical efficacy against infections caused by these fungal pathogens.
Wiederhold et al. (2026) studied this question.