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In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus

Karen Joy Shaw1, Wiley A Schell2, Jonathan Covel3

  • 1Amplyx Pharmaceuticals, San Diego, California, USA kshaw@amplyx.com.

Antimicrobial Agents and Chemotherapy
|June 13, 2018
PubMed

Insights

New antifungal compounds targeting Gwt1 show potent activity against Cryptococcus neoformans and Cryptococcus gattii. Combination therapy with APX001 and fluconazole significantly reduced fungal burden in a cryptococcal meningitis model.

Area of Science:

  • Mycology
  • Infectious Diseases
  • Pharmacology

Background:

  • Cryptococcal meningitis (CM) is a life-threatening fungal infection with limited treatment options and high mortality, particularly in resource-poor settings.
  • Current therapies for CM are insufficient, necessitating the development of novel antifungal agents.
  • APX001A and its prodrug APX001 are novel compounds targeting the essential fungal enzyme Gwt1, crucial for cell wall integrity.

Purpose of the Study:

  • To evaluate the in vitro and in vivo antifungal activity of Gwt1 inhibitors, including APX001A and APX001, against Cryptococcus species.
  • To assess the synergistic potential of Gwt1 inhibitors in combination with fluconazole for CM treatment.
  • To determine the efficacy of Gwt1 inhibitors in reducing fungal burden in a preclinical model of cryptococcal meningitis.

Main Methods:

  • In vitro susceptibility testing (MIC determination) of Gwt1 inhibitors against Cryptococcus neoformans and Cryptococcus gattii.
  • In vitro synergy testing of APX001A and APX2020 with fluconazole using the fractional inhibitory concentration index (FICI).
  • In vivo efficacy studies in a murine model of cryptococcal meningitis, evaluating fungal burden in brain and lung tissues after treatment with Gwt1 inhibitors and/or fluconazole.

Main Results:

  • Gwt1 inhibitors exhibited low minimum inhibitory concentrations (MICs) against C. neoformans and C. gattii, ranging from 0.004 to 0.5 μg/ml.
  • APX001A and APX2020 demonstrated significant in vitro synergy with fluconazole (FICI = 0.37).
  • Combination therapy with APX001 and fluconazole resulted in a substantial reduction (3.52 log10 CFU/g) in fungal burden in brain tissue compared to monotherapy.
  • Another Gwt1 inhibitor prodrug, APX2096, showed dose-dependent efficacy, leading to near-complete or complete sterilization of lung and brain tissues at higher doses in the CM model.

Conclusions:

  • Gwt1 inhibitors, including APX001A and APX001, possess potent in vitro and in vivo activity against Cryptococcus species relevant to CM.
  • The combination of Gwt1 inhibitors with fluconazole offers a promising synergistic therapeutic strategy for CM.
  • These findings support the further clinical development of Gwt1 inhibitors as a new class of antifungal agents for invasive fungal infections like CM.
Keywords:
1-aminobenzotriazoleAPX001APX001ACryptococcusGwt1antifungalinfection model

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