title: 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.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Yoon-Dong
authors.initials: YD
authors.lastname: Park
authors.forename: Janyce A
authors.initials: JA
authors.lastname: Sugui
authors.forename: Annette
authors.initials: A
authors.lastname: Fothergill
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Kyung J
authors.initials: KJ
authors.lastname: Kwon-Chung
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000666:Amphotericin B / Q000737:chemistry; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001203:Ascomycota / Q000187:drug effects*; D001735:Bithionol / Q000737:chemistry; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D058492:Drug Repositioning / Q000379:methods*; D005467:Floxuridine / Q000737:chemistry; D006801:Humans; D025301:Hyphae / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy; D013172:Spores, Fungal / Q000187:drug effects; D016559:Tacrolimus / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D005467:Floxuridine; C101425:posaconazole; D000666:Amphotericin B; D000255:Adenosine Triphosphate; D001735:Bithionol; D016559:Tacrolimus