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In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2018 Jul 27; Vol. 62 (8). Date of Electronic Publication: 2018 Jul 27 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- 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 log <subscript>10</subscript> CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log <subscript>10</subscript> 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 log <subscript>10</subscript> CFU/g lung tissue and from 7.00 and 0.92 log <subscript>10</subscript> 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.<br /> (Copyright © 2018 Shaw et al.)
- Subjects :
- Administration, Oral
Amidohydrolases genetics
Amidohydrolases metabolism
Aminopyridines chemical synthesis
Aminopyridines pharmacokinetics
Animals
Antifungal Agents chemical synthesis
Antifungal Agents pharmacokinetics
Brain drug effects
Brain microbiology
Cryptococcus gattii drug effects
Cryptococcus gattii enzymology
Cryptococcus gattii genetics
Cryptococcus gattii growth & development
Cryptococcus neoformans enzymology
Cryptococcus neoformans genetics
Cryptococcus neoformans growth & development
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Combinations
Drug Synergism
Fluconazole pharmacology
Fungal Proteins genetics
Fungal Proteins metabolism
Humans
Injections, Intraperitoneal
Isoxazoles chemical synthesis
Isoxazoles pharmacokinetics
Lung drug effects
Lung microbiology
Male
Meningitis, Cryptococcal microbiology
Mice
Microbial Sensitivity Tests
Organophosphates chemical synthesis
Organophosphates pharmacokinetics
Prodrugs chemical synthesis
Prodrugs pharmacokinetics
Amidohydrolases antagonists & inhibitors
Aminopyridines pharmacology
Antifungal Agents pharmacology
Cryptococcus neoformans drug effects
Fungal Proteins antagonists & inhibitors
Isoxazoles pharmacology
Meningitis, Cryptococcal drug therapy
Organophosphates pharmacology
Prodrugs pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 62
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 29891599
- Full Text :
- https://doi.org/10.1128/AAC.00523-18