New applications for known drugs: Human glycogen synthase kinase 3 inhibitors as modulators of Aspergillus fumigatus growth

Abstract

Invasive aspergillosis (IA) is one of the most severe forms of fungi infection. IA disease is mainly due to Aspergillus fumigatus, an air-borne opportunistic pathogen. Mortality rate caused by IA is still very high (50-95%), because of difficulty in early diagnostics and reduced antifungal treatment options, thus new and efficient drugs are necessary. The aim of this work is, using Aspergillus nidulans as non-pathogen model, to develop efficient drugs to treat IA. The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. With the aim to identify effective inhibitors of colonial growth of A. fumigatus we use A. nidulans as an accurate model for in vivo and in silico studies. Several well-known human GSK-3β inhibitors were tested for inhibition of A. nidulans colony growth. Computational tools as docking studies and binding site prediction was used to explain the different biological profile of the tested inhibitors. Three of the five tested hGSK3β inhibitors are able to reduce completely the colonial growth by covalent bind to the enzyme. Therefore these compounds may be useful in different applications to eradicate IA.

Lung colonization by Aspergillus fumigatus is controlled by ZNF77

“…No host-derived growth promotion factors have been described previously for moulds although factors modulating bacterial and Candida growth have been observed 45 – 47 . The only host factors described that might modulate Aspergillus germination and growth are limited to human glycogen synthase kinase 3 activity, corticosteroid treatment or smoking status 13 , 48 , 49 .…”

Protein Kinase A and High-Osmolarity Glycerol Response Pathways Cooperatively Control Cell Wall Carbohydrate Mobilization in Aspergillus fumigatus

“…In addition, A. fumigatus glycogen synthase kinase has been proposed to be a target for treating invasive aspergillosis as it is important for Aspergillus growth (35).…”

The High Osmolarity Glycerol Mitogen-Activated Protein Kinase regulates glucose catabolite repression in filamentous fungi

“…Similar Gsk3 inhibitor compounds have already been shown as inhibiting A . nidulans growth [ 50 ]. First of all, the minimal inhibitory concentration (MIC) of IgskA was determined.…”

“…To further determine and confirm the regulation of PbsA by GskA, we performed several experiments with the GskA inhibitor Gsk3β inhibitor VII (IgskA), as deletion of gskA results in a strain that is severely growth compromised. Similar Gsk3 inhibitor compounds have already been shown as inhibiting A. nidulans growth [50]. First of all, the minimal inhibitory concentration (MIC) of IgskA was determined.…”