Fig. 8: Model of NPD827 mechanism of action. | Nature Communications

Fig. 8: Model of NPD827 mechanism of action.

From: Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation

Fig. 8: Model of NPD827 mechanism of action.The alternative text for this image may have been generated using AI.

(Left) Under normal physiological conditions, ergosterol and sphingolipids exist within the plasma membrane as lipid microdomains (yellow shadow). These microdomains harbor membrane-bound proteins, including drug-efflux pumps such as Cdr1. (Middle) NPD827 inserts into the plasma membrane and alters the biophysical properties of the membrane, reducing lateral mobility and impairing the function of membrane-bound proteins (i.e., Cdr1). Internalization of NPD827-associated membrane fragments disrupts the endomembrane system and induces vacuolar fragmentation, thereby perturbing lipid recycling throughout the cell. This disruption results in accumulation of toxic long-chain sphingoid bases, depletion of downstream sphingolipids, such as OH-Ceramide and Glucosylceramide, and induction of membrane-associated stress responses (i.e., lipid droplets, UPR, calcineurin-dependent stress responses). (Right) Due to impairment of drug-efflux by Cdr1, fluconazole accumulates within the cell further perturbing lipid homeostasis. The combination of effects ultimately halts growth of C. albicans in a synergistic manner.

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