The combination of manogepix and itraconazole is synergistic and inhibits the growth of Madurella mycetomatis
Detailed study abstract:Mycetoma is a neglected tropical disease commonly caused by the fungus Madurella mycetomatis. Standard treatment consists of treatment with itraconazole for a long period of time in combination with surgical excision of the infected tissue but has a low success rate. To improve treatment outcomes novel treatment strategies are needed. Here we determined the potential of manogepix a novel antifungal agent which targets the GPI-anchor biosynthesis pathway by inhibition of the GWT1 enzyme. Manogepix was evaluated by 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 checkerboard assay. The efficacy of clinically relevant dosages was assessed in an in vivo grain model in Galleria mellonella larvae. In vitro MICs for manogepix ranged from  lower than0.008 to greater than 8 µg/mL and 16/22 M. mycetomatis strains had a MIC greater than 4 mg/mL. Differences in MICs were not related to differences observed in the GWT1 protein sequence. Overall 4 µg/mL was required for 50% growth inhibition. For 70% of the tested isolates synergism was found between manogepix and itraconazole in vitro. In vivo we did not observe enhanced survival upon admission of 8.6 mg/kg manogepix as monotherapy nor in combination treatment with 5.7 mg/kg itraconazole. MICs of manogepix were high but the in vitro antifungal activity of itraconazole was enhanced in combination therapy. However no efficacy of manogepix was found in an in vivo grain model using clinically relevant dosages. Therefore the therapeutic potential of manogepix in mycetoma caused by M. mycetomatis seems limited.