[en] 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 MIC50 values of 2.875 and 6.143 μg/ml, respectively) and against L. prolificans isolates (mean MIC50 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.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Yaakoub, Hajar; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France
Staerck, Cindy ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire ; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France
Mina, Sara; Department of Medical Laboratory Sciences, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
Godon, Charlotte; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France
Fleury, Maxime; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France
Bouchara, Jean-Philippe; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France ; Département de biologie des agents infectieux , Laboratoire De Parasitologie-Mycologie, Centre Hospitalier Universitaire, Angers, France
Calenda, Alphonse; Groupe d'Etude Des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut De Biologie En Santé-IRIS, CHU Angers,Angers, France
Language :
English
Title :
Repurposing of auranofin and honokiol as antifungals against Scedosporium species and the related fungus Lomentospora prolificans.
MJJF, JPB and AC are members of the ECMM/ISHAM (European Confederation of Medical Mycology/International Society for Human and Animal Mycology) working group Fungal respiratory infections in Cystic Fibrosis (Fri-CF). For her PhD thesis, Cindy Staerck was recipient of a grant from our national patient organization against cystic fibrosis, Vaincre la Mucoviscidose, which is gratefully acknowledged. Some experiments were performed owing to the financial support from our local patient organization against cystic fibrosis Anjou Muco which is also acknowledged.
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