Related Experiment Video
Updated: Feb 2, 2026
Experimental Model to Evaluate Resolution of Pneumonia
Published on: February 17, 2023
APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia
Suganya Viriyakosol1, Mili Kapoor2, Sharon Okamoto3
1VA Healthcare, San Diego, California, USA.
Abstract:
Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis and C. posadasii, that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extrapulmonary sites of infection are very difficult to treat and often require lifelong azole therapy. APX001A is the first in a new class of broad-spectrum antifungal agents that inhibit Gwt1, an enzyme which is required for cell wall localization of glycosylphosphatidylinositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, 2 h after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001- and APX2097-treated mice survived significantly longer than control and fluconazole-treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.
Insights
A new antifungal drug, APX001, shows promise for treating coccidioidomycosis, a serious fungal infection. It effectively reduced fungal load and improved survival in mice, offering a potential new therapy for this difficult-to-treat disease.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Coccidioidomycosis is a systemic fungal infection endemic to the southwestern US, caused by *Coccidioides* species.
- Chronic and disseminated forms are challenging to treat, often necessitating long-term azole therapy.
- Existing treatments have limitations, highlighting the need for novel antifungal agents.
Purpose of the Study:
- To evaluate the efficacy of APX001, a novel Gwt1 inhibitor, and its prodrug analog APX2097 against *Coccidioides* fungal infections.
- To assess the therapeutic potential of APX001 in a murine model of coccidioidomycosis.
Main Methods:
- APX001 and APX2097 were tested against clinical isolates of *Coccidioides*, measuring hyphal growth inhibition.
- A murine model of coccidioidomycosis was used, with mice treated orally with APX001 or APX2097 after administration of a P450 inhibitor.
- Efficacy was assessed by measuring lung colony counts, dissemination, and survival rates, comparing results to fluconazole treatment.
Main Results:
- APX001 and analogs demonstrated high activity against *Coccidioides* isolates, inhibiting hyphal growth at low nanogram/ml concentrations.
- Treatment with APX001 or APX2097 in mice significantly reduced lung fungal burden and prevented dissemination.
- Mice treated with APX001 and APX2097 exhibited significantly improved survival compared to control and fluconazole groups.
Conclusions:
- APX001, a novel Gwt1 inhibitor, and its prodrug analog APX2097 show potent antifungal activity against *Coccidioides*.
- These agents are effective in a murine model of coccidioidomycosis, reducing fungal load and improving survival.
- APX001 represents a promising new therapeutic candidate for coccidioidomycosis and other invasive fungal infections.
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