Repurposing of auranofin and honokiol as antifungals against Scedosporium species and the related fungus Lomentospora prolificans

Abstract

The slowing-down de novo drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory microorganisms, such as Scedosporium species and Lomentospora prolificans. Recent studies on Scedosporium responses to oxidative stress underscored the importance of targeting the underlying mechanisms. Auranofin, ebselen, PX-12, honokiol, and to a lesser extent, conoidin A are known to disturb redox-homeostasis systems in many organisms. Their antifungal activity was assessed against 27 isolates belonging to the major Scedosporium species: S. apiospermum, S. aurantiacum, S. boydii, S. dehoogii, S. minutisporum, and Lomentospora prolificans. Auranofin and honokiol were the most active against all Scedosporium species (mean MIC 50 values of 2.875 and 6.143 μg/ml, respectively) and against L. prolificans isolates (mean MIC 50 values of 4.0 and 3.563μg/ml respectively). Combinations of auranofin with voriconazole or honokiol revealed additive effects against 9/27 and 18/27 isolates, respectively. Synergistic interaction between auranofin and honokiol was only found against one isolate of L. prolificans. The effects of auranofin upon exposure to oxidative stress were also investigated. For all species except S. dehoogii, the maximal growth in the presence of auranofin significantly decreased when adding a sublethal dose of menadione. The analysis of the expression of genes encoding oxidoreductase enzymes upon exposure of S. apiospermum to honokiol unveiled the upregulation of many genes, especially those coding peroxiredoxins, thioredoxin reductases, and glutaredoxins. Altogether, these data suggest that auranofin and honokiol act via dampening the redox balance and support their repurposing as antifungals against Scedosporium species and L. prolificans.

Identification of Promising Antifungal Drugs against Scedosporium and Lomentospora Species after Screening of Pathogen Box Library

“…Whereas the antifungal activity of iodoquinol has only been demonstrated recently by studies using the Pathogen Box [ 40 , 41 , 42 , 58 ], the antifungal effect of auranofin has already been described in the literature for a variety of fungal pathogens, such as Candida species, C. neoformans , Blastomyces dermatitidis , Aspergillus fumigatus, and Rhizopus oryzae [ 59 , 60 ]. It has also been shown that auranofin is a promising repurposing drug to treat Scedosporium and Lomentospora infections, presenting minimal inhibitory concentrations ranging from 2 to >16 µg/mL [ 61 ].…”

“…TrxR is present in a variety of cell models, such as mammalian cells, protozoans, bacteria, plants, and fungi, and its inhibition by auranofin has already been demonstrated in different cell models, including Entoameba histolytica , Staphylococcus aureus , and fungi [ 63 , 64 ]. Auranofin has already been shown to primarily inhibit TrxR by irreversible binding to the selenocysteinyl residue, but its exact mode of action is still unclear [ 61 ]. In fungi, TrxR was found to be essential for C. neoformans viability and to play a role in responding to oxidative stress in C. albicans , Saccharomyces cerevisiae , and A. fumigatus .…”

“…Thus, its inhibition by auranofin leads to a higher fungal sensitivity to oxidative stress [ 59 , 64 ]. Scedosporium species are known to possess more than 30 genes encoding putative antioxidant enzymes, especially those encoding TrxRs, which is one reason for their high resistance to antifungal agents [ 61 ]. Thus, its inhibition by auranofin might be an important mechanism of action and a promising approach to impair Scedosporium growth.…”

“…In addition, a synergistic effect was observed between iodoquinol and caspofungin. In C. albicans and C. neoformans , an additive effect of auranofin with fluconazole and amphotericin B has already been demonstrated [ 62 ], and an additive interaction has been found with voriconazole in Scedosporium and Lomentospora species [ 61 ]. However, these observations were detected only against a limited number of isolates, indicating that more studies are needed to understand how auranofin interacts with the antifungal drugs currently available in clinical settings.…”

Target‐based drug repurposing against Candida albicans—A computational modeling, docking, and molecular dynamic simulations study

“…Stylianou et al, 52 and Fuchs et al, 53 observed the inhibition of planktonic growth of C. albicans after Aurnafin administration 52,53 . Yaakoub et al, 54 demonstrated the inhibitory effect of Aurnafin in combination with Honokiol or Voriconazole on 9/27 and 18/27 fungal species of Scedosporium , respectively 54 55 reported no effect of Aurnafin on C. albicans 55 .…”