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  • Glycosylphosphatidylinositol GPI cell wall anchor synthesis

    2024-05-25

    Glycosylphosphatidylinositol (GPI) UCB 35625 anchor synthesis pathway is another promising antifungal target. Novel inhibitors of Gwt1 and Mcd4, two enzymes in the GPI anchor pathway were identified by the chemical-genomics-based screening platform CaFT (Candida albicans fitness test) [89]. Screening was performed against more than 1000 synthetic compounds known to inhibit C. albicans growth but for which their drug target and mechanism of action were unknown. Two compounds, G884 and G365 were identified as Gwt1 inhibitors. Both showed activity against C. albicans and only G365 displayed strong activity against A. fumigatus. M743 was identified under screening of natural products extracts. This compound and its semisynthetic derivative M720 are specific inhibitors of Mcd4 and displayed a potent activity against many Candida and Aspergillus species. The use of CaFT and other genetic platforms, such as the S. cerevisiae haploinsufficiency profiling (HOP) that offer specific assays for all possible drug targets in yeast [8] will continue to be extremely helpful in the discovery and mechanism of action of novel antifungals. Chemical genomics-based approaches have been used to identify FDA-approved compounds that potentiate the fluconazole activity against several yeasts [90]. An antifungal combination matrix was developed to analyze around 86,000 chemical interactions between 3600 small molecules and 6 approved antifungal drugs against four species of fungi [91]. A susceptibility test against fluconazole-resistant isolate of C. albicans unveiled combinations capable of potentiating fluconazole activity in this strain. These authors also found that combinations of clofazimine, a compound with unreported antifungal activity, with several antifungals exhibited activity against several fungal pathogens. A large gene deletion library in C. neoformans and a decision-guiding process were used to identify and analyze gene-drug interactions that could help to find drugs that act synergistically against C. neoformans[92]. Gene drug interactions were identified for over 80% of the 1500 gene deletion strains tested. Interestingly, data from C. neoformans were compared with those obtained with S. cerevisiae, results revealed very few conserved responses. Kaltdorf et al. (2016) [93] using bioinformatics tools have identified 64 targets in Aspergillus fumigatus that will be evaluated for antifungal development. These targets include metabolic enzymes involved in vitamins, lipids or amino acids biosynthesis that do not have close orthologs in humans. Other strategies that are being followed to find new specific fungal targets are those based on transcriptome studies in A. fumigatus focused on identify invasion-related gene expression changes [94] and detailed analyses of protein-protein interactions in fungal infections [95]. Historically, the most common approach for identifying antifungal molecules has been screening large libraries of synthetic small molecules or natural products [1], [8], [96]. Indeed, two approved antifungal drug classes, the echinocandins and polyenes, were discovered by screening of natural products. Very recently a couple of examples related to this strategy have been reported. Psoriasin, a small fungicidal protein active against various filamentous fungi including Trichophyton rubrum and A. fumigatus, but not against C. albicans was isolated from lesional psoriasis scale extracts [97]. Psoriasin works by chelating free intracellular zinc leading to fungal apoptosis. Thus, selective fungal cell-penetrating zinc-chelators could be a new approach to find new antifungal agents. Humidimycin, a ring peptide produced by Streptomyces humidus that improves the antifungal activity of caspofungin by 10-fold was identified from the screening of a collection of 20,000 microbial extracts [98]. Humidimycin acts by inhibiting the fungal high osmolarity glycerol (HOG) response pathway, reducing the protective stress response induced by caspofungin [98]. As the HOG pathway is not present in human cells, humidimycin is not toxic, resulting in a promising drug.