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- W4387095222 abstract "Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure-activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure-activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics." @default.
- W4387095222 created "2023-09-28" @default.
- W4387095222 creator A5032907078 @default.
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- W4387095222 date "2023-09-27" @default.
- W4387095222 modified "2023-10-15" @default.
- W4387095222 title "Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against <i>Candida auris</i>" @default.
- W4387095222 cites W1632467620 @default.
- W4387095222 cites W2019836506 @default.
- W4387095222 cites W2036731916 @default.
- W4387095222 cites W2064795801 @default.
- W4387095222 cites W2092294469 @default.
- W4387095222 cites W2100721452 @default.
- W4387095222 cites W2111483559 @default.
- W4387095222 cites W2152713010 @default.
- W4387095222 cites W2154669492 @default.
- W4387095222 cites W2261682386 @default.
- W4387095222 cites W2325495180 @default.
- W4387095222 cites W2520580617 @default.
- W4387095222 cites W2524164784 @default.
- W4387095222 cites W2536287248 @default.
- W4387095222 cites W2538410300 @default.
- W4387095222 cites W2616391082 @default.
- W4387095222 cites W2621317116 @default.
- W4387095222 cites W2750959598 @default.
- W4387095222 cites W2767031614 @default.
- W4387095222 cites W2782394839 @default.
- W4387095222 cites W2794059815 @default.
- W4387095222 cites W2800526695 @default.
- W4387095222 cites W2885698573 @default.
- W4387095222 cites W2895998698 @default.
- W4387095222 cites W2899930511 @default.
- W4387095222 cites W2900853140 @default.
- W4387095222 cites W2908919171 @default.
- W4387095222 cites W2911930377 @default.
- W4387095222 cites W2912182456 @default.
- W4387095222 cites W2922422721 @default.
- W4387095222 cites W2945540290 @default.
- W4387095222 cites W2950379126 @default.
- W4387095222 cites W2950895583 @default.
- W4387095222 cites W2951263089 @default.
- W4387095222 cites W2951788850 @default.
- W4387095222 cites W2951867871 @default.
- W4387095222 cites W2953431223 @default.
- W4387095222 cites W2956528092 @default.
- W4387095222 cites W2962874894 @default.
- W4387095222 cites W2973870124 @default.
- W4387095222 cites W2991460964 @default.
- W4387095222 cites W3000334428 @default.
- W4387095222 cites W3006511740 @default.
- W4387095222 cites W3012011716 @default.
- W4387095222 cites W3016937378 @default.
- W4387095222 cites W3025932998 @default.
- W4387095222 cites W3046120299 @default.
- W4387095222 cites W3081020009 @default.
- W4387095222 cites W3092629252 @default.
- W4387095222 cites W3092866133 @default.
- W4387095222 cites W3093074147 @default.
- W4387095222 cites W3093683101 @default.
- W4387095222 cites W3102866798 @default.
- W4387095222 cites W3103232086 @default.
- W4387095222 cites W3137591649 @default.
- W4387095222 cites W3145703097 @default.
- W4387095222 cites W3146610711 @default.
- W4387095222 cites W3158113378 @default.
- W4387095222 cites W3164396346 @default.
- W4387095222 cites W3176060925 @default.
- W4387095222 cites W3186309583 @default.
- W4387095222 cites W3186384872 @default.
- W4387095222 cites W3187612454 @default.
- W4387095222 cites W3194477778 @default.
- W4387095222 cites W3201661857 @default.
- W4387095222 cites W4200011148 @default.
- W4387095222 cites W4200124722 @default.
- W4387095222 cites W4200371066 @default.
- W4387095222 cites W4206237820 @default.
- W4387095222 cites W4224855950 @default.
- W4387095222 cites W4280637873 @default.
- W4387095222 cites W4282032913 @default.
- W4387095222 cites W4283514431 @default.
- W4387095222 cites W4289522338 @default.
- W4387095222 cites W4295278528 @default.
- W4387095222 cites W4297229549 @default.
- W4387095222 cites W4303959045 @default.
- W4387095222 cites W4307431329 @default.
- W4387095222 cites W4307770999 @default.
- W4387095222 cites W4311791743 @default.
- W4387095222 cites W4377046861 @default.
- W4387095222 cites W4384559034 @default.
- W4387095222 doi "https://doi.org/10.1021/acsinfecdis.3c00199" @default.
- W4387095222 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37756147" @default.
- W4387095222 hasPublicationYear "2023" @default.
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