Sulfonium-modified pneumocandins overcome Cryptococcus' intrinsic echinocandin resistance
- Covalent sulfonium modification of the natural pneumocandin B0 scaffold gave derivatives active against Candida and able to reverse innate Cryptococcus neoformans resistance (MIC as low as 2 μg/mL).
- The modification raised fungal membrane permeability and caused depolarization while strengthening glucan synthase inhibition.
- Leads 3h and 5h showed low resistance potential, good safety and PK, and in vivo antifungal efficacy.
💡 Points
Echinocandins have never covered Cryptococcus, so adding a membrane-active cationic handle to restore activity is a smart reuse of a validated scaffold. The risk is that membrane disruption narrows the selectivity window, so host-cell toxicity data and the mechanism split deserve a close read.