In vitro and in vivo Evaluation of APX001A/APX001 and other Gwt1 inhibitors against Cryptococcus [PublishAheadOfPrint]

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 invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidyl inositol (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 (FICI 0.37). In a CM model, APX001 and fluconazole each, alone, reduced log₁₀ colony forming units (CFU)/g brain (0.78 and 1.04, respectively), whereas the combination resulted in a reduction of 3.52 log₁₀ CFU/g brain.

Efficacy as measured by a reduction in brain and lung fungal burden was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose dependent reductions in fungal burden ranged between 5.91 and 1.79 log₁₀ CFU/g lung and between 7.00 and 0.92 log₁₀ CFU/g brain, representing near or complete sterilization of lung and brain tissue at the higher doses. These data support further clinical evaluation of this new class of antifungal agents for CM.

https://ift.tt/2sNxRBG