Rapid Identification of Antifungal Compounds against Exserohilum rostratum Using High Throughput Drug Repurposing Screens

Abstract

A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

Emerging therapies targeting the ubiquitin proteasome system in cancer

“…Additionally, the NIH and Pharma have embarked on a coordinated effort to "repurpose" abandoned drugs proven safe in phase I trials to accelerate therapeutic development (70). There are already examples of successful identification of relevant novel drug activity through this initiative (71,72). Indeed there may be many compounds already in existence with unrecognized activity against the UPS (as was the case for the IMiDs).…”

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

“…Following a repurposing phenotypic screen, new indications for existing drugs may be rapidly identified and clinical trials can be carried out quickly, which is especially critical for rapidly spreading infectious diseases. For example, recent drug repurposing screens have led to discoveries of potential new candidate therapies for Ebola virus disease 30,31 , Giardiasis 32 , Entamoeba histolytica infection 33 , malaria gametocytes 34 , Exserohilum rostratum infection 35 , hepatitis C virus infection 36 , and, very recently, ZIKV infection 37 . Based on our previous finding that ZIKV infection of hNPCs results in an increase of caspase-3 activation, followed by cell death 15 , we designed a compound screening approach using caspase-3 activity as the primary screening assay, and a secondary cell viability assay for confirmation (Supplementary Fig.…”

Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

“…The present study was prompted by the identification of bithionol as a potential fungicidal agent in a large repurposing screen ( 17 ) and by multiple reports for humans suggesting high serum drug levels and low toxicity ( 11 ), as well as also bithionol’s potential utility in treating CNS infections ( 18 ). The further studies described here confirmed bithionol as a potentially useful antifungal agent against Cryptococcus neoformans due to its antifungal effects, suggesting its utility in identifying the antifungal target of this agent, for which few data are available regarding its activity in fungi.…”