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. IMPORTANCE Fosmanogepix (prodrug of manogepix) is a novel antifungal agent with a new mechanism of action and broad-spectrum activity, including against yeasts and molds. It is currently in two Phase 3 clinical trials for the treatment of invasive candidiasis and invasive mold infections and has previously been used for the treatment of Fusarium spp. infections during an outbreak. There are three main antifungal classes (echinocandins, azoles, and polyenes), but only azoles and amphotericin B have activity against non- Aspergillus molds; therefore, novel antifungal agents are urgently needed because invasive fungal infections have high morbidity and mortality rates. Here, we look at the in vitro activity of manogepix and comparator antifungal agents against non- Aspergillus fumigatus mold isolates collected from patient infections in 2023 and 2024. Manogepix showed potent in vitro activity against these organisms, with similar to or better activity than that of the comparators against most organism groups, and represents a promising potential future treatment option.