The ubiquitous and essential V-ATPase is a worthy chemotherapeutic target in the escalating battle against invasive
fungal infections. Pathogenic fungi require optimum V-ATPase function for secretion of virulence factors, induction
of stress response pathways, hyphal morphology and homeostasis of pH and other cations in order to successfully
survive within and colonize the host. This review discusses why impairment of V-ATPase activity confers multidrug sensitivity
and loss of virulence. Recent evidence points to the V-ATPase as a novel downstream target of the azole class of
antifungals that inhibit the biogenesis of ergosterol. Depletion of ergosterol from vacuolar membranes led to progressive
alkalization of yeast vacuoles, loss of V-ATPase activity and growth inhibition that could be rescued by exogenous ergosterol
feeding. Other studies point to a critical role for sphingolipids, phospholipids and cardiolipin in V-ATPase function.
Thus, drugs that inhibit the V-ATPase directly, or indirectly by modulating the membrane milieu, can profoundly affect
fungal viability and virulence. These findings justify a systematic screen for fungal specific V-ATPase inhibitors or membrane
active compounds that can be used in antifungal chemotherapy.
Keywords: H+-ATPase, vacuolar ATPase, fluconazole, ergosterol, amiodarone, pH, fungal infection, Invasive fungal infections, Mucosal, antifungal drugs, Fluoropyrimidines
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