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

Publication ,  Journal Article
Shaw, KJ; Schell, WA; Covel, J; Duboc, G; Giamberardino, C; Kapoor, M; Moloney, M; Soltow, QA; Tenor, JL; Toffaletti, DL; Trzoss, M; Webb, P ...
Published in: Antimicrob Agents Chemother
August 2018

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against both C. neoformans and C. gattii APX001A and APX2020 demonstrated in vitro synergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10 CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10 CFU/g lung tissue and from 7.00 and 0.92 log10 CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

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Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

August 2018

Volume

62

Issue

8

Location

United States

Related Subject Headings

  • Prodrugs
  • Organophosphates
  • Microbiology
  • Microbial Sensitivity Tests
  • Mice
  • Meningitis, Cryptococcal
  • Male
  • Lung
  • Isoxazoles
  • Injections, Intraperitoneal
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Shaw, K. J., Schell, W. A., Covel, J., Duboc, G., Giamberardino, C., Kapoor, M., … Perfect, J. R. (2018). In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus. Antimicrob Agents Chemother, 62(8). https://doi.org/10.1128/AAC.00523-18
Shaw, Karen Joy, Wiley A. Schell, Jonathan Covel, Gisele Duboc, C. Giamberardino, Mili Kapoor, Molly Moloney, et al. “In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.Antimicrob Agents Chemother 62, no. 8 (August 2018). https://doi.org/10.1128/AAC.00523-18.
Shaw KJ, Schell WA, Covel J, Duboc G, Giamberardino C, Kapoor M, et al. In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus. Antimicrob Agents Chemother. 2018 Aug;62(8).
Shaw, Karen Joy, et al. “In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.Antimicrob Agents Chemother, vol. 62, no. 8, Aug. 2018. Pubmed, doi:10.1128/AAC.00523-18.
Shaw KJ, Schell WA, Covel J, Duboc G, Giamberardino C, Kapoor M, Moloney M, Soltow QA, Tenor JL, Toffaletti DL, Trzoss M, Webb P, Perfect JR. In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus. Antimicrob Agents Chemother. 2018 Aug;62(8).

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

August 2018

Volume

62

Issue

8

Location

United States

Related Subject Headings

  • Prodrugs
  • Organophosphates
  • Microbiology
  • Microbial Sensitivity Tests
  • Mice
  • Meningitis, Cryptococcal
  • Male
  • Lung
  • Isoxazoles
  • Injections, Intraperitoneal