The combination of manogepix and itraconazole is synergistic and inhibits the growth of Madurella mycetomatis in vitro but not in vivo

Mycetoma is a neglected tropical disease commonly caused by the fungus Madurella mycetomatis. Standard treatment consists of extensive treatment with itraconazole in combination with surgical excision of the infected tissue, but has a low success rate. To impro v e treatment outcomes, no v el treatment strategies are needed. Here, we determined the potential of manogepix, a novel antifungal agent that targets the GPI-anchor biosynthesis pathway by inhibition of the GWT1 enzyme. Manogepix w as evaluated b y determining the minimal inhibitory concentrations (MICs) according to the CLSI-based in vitro susceptibility assay for 22 M. mycetomatis strains and by in silico protein comparison of the target protein. The synergy between manogepix and itraconazole was determined using a c hec kerboard assay. The efficacy of clinically rele v ant dosages was assessed in an in vivo grain model in Galleria mellonella larvae. MICs for manogepix ranged from < 0.008 to > 8 mg/l and 16/22 M. m y cetomatis strains had an MIC >= 4 mg/ml. Differences in MICs were not related to differences observed in the GWT1 protein sequence. For 70% of the tested isolates, synergism was found between manogepix and itraconazole in vitro . In vivo , enhanced survival was not observed upon admission of 8.6 mg/kg manogepix, nor in combination treatment with 5.7 mg/kg itraconazole. MICs of manogepix were high, but the in vitro antifungal activity of itraconaz ole w as enhanced in combination therapy. However, no efficacy of manogepix was found in an in vivo grain model using clinically relevant dosages. T heref ore, the therapeutic potential of manogepix in mycetoma caused by M. mycetomatis seems limited.

Automated summary

Mycetoma is a neglected tropical disease caused by the fungus Madurella mycetomatis. This study evaluated the potential of a novel antifungal agent, manogepix, for the treatment of mycetoma. In vitro tests showed synergy between manogepix and itraconazole, but no efficacy was observed in an in vivo grain model using clinically relevant dosages. The therapeutic potential of manogepix for mycetoma caused by M. mycetomatis appears to be limited.