Activity of manogepix and comparator antifungal agents against uncommon filamentous fungal isolates collected in a global surveillance program

Fosmanogepix (prodrug of manogepix) is a novel antifungal agent targeting the Gwt1 enzyme. This agent has activity against a diverse spectrum of fungal species, including species refractory to other antifungal classes or multidrug-resistant fungi. A total of 332 molds from a worldwide surveillance study were susceptibility tested for manogepix and comparator antifungal agents by the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method. Wild-type upper limit (WT-UL) values were determined for manogepix against organism groups using cumulative surveillance data. Isolates were collected from 20 countries, 41 hospitals, and 7 different infection sources. Eighteen genera were represented. Isolates included 208 non- fumigatus Aspergillus spp.; 37.3% (124 isolates) were non- Aspergillus molds. The manogepix minimum effective concentration (MEC _50/90 ) was lower than the MIC _50/90 for azole comparators or amphotericin B against all Aspergillus spp., Fusarium spp., Scedosporium spp., Lomentospora spp., Mucor spp., and Penicillium spp. Only Rhizopus spp. had higher MEC _50/90 values for manogepix than the MIC _50/90 values of the comparators. The WT-UL values reflected this, with the highest values for Rhizopus spp. at 16 mg/L and Mucor spp. at 4 mg/L, while they were ≤0.12 mg/L for all other organisms. Between 2023 and 2024, there were no organisms with MECs for manogepix above the WT-UL value. Manogepix displayed robust in vitro activity against contemporary non- Aspergillus fumigatus mold isolates. This agent was more potent than azole comparators or amphotericin B against most organism groups. Historically, less than 5% of isolates tested ( n = 19) had MECs above the WT-UL cutoff values. These data support the continued development of manogepix for the treatment of mold infections.