A drug-repurposing screen of FDA- and EMA-approved drugs identifies two NF-κB inhibitors active against eumycetoma.

Background: Mycetoma caused by Madurella mycetomatis (eumycetoma) is a neglected tropical disease that forms tumorous lesions in the subcutaneous tissue. The current standard treatment for eumycetoma consists of antifungal treatment combined with surgery, with limited success rates. Due to lack of investment, there are currently no large drug discovery programmes for mycetoma. Repurposing screening can therefore offer an effective and economical way to identify drugs that can be effective in eumycetoma treatment. Therefore, in this study we determined the in vitro activity and in vivo efficacy of 5631 compounds present in the Oncode Drug Repurposing library.

Methods: In total, 5631 drugs from the Oncode Drug Repurposing library were screened for in vitro activity against M. mycetomatis using a CLSI-based in vitro susceptibility assay and CellTiter-Glo as a viability dye. Compounds that inhibited the metabolic activity were tested for in vivo activity in M. mycetomatis-infected Galleria mellonella larvae.

Results: Twenty-eight compounds out of the 5631 drugs were able to inhibit the metabolic activity of M. mycetomatis at 2 µM. Seventeen of the 28 compounds were azoles and 2 were toxic to G. mellonella and therefore not screened further. Two from the remaining 9 compounds, bay117085 (log-rank, P = 0.0494) and IMD-0354 (log-rank, P = 0.0043), prolonged the survival of M. mycetomatis-infected larvae. Both compounds were designed as NF-κB inhibitors.

Conclusions: NF-κB inhibitors bay117085 and IMD-0354 were able to prolong the survival of M. mycetomatis-infected larvae.