Department of Physiology, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Curr Protein Pept Sci. 2012 Mar;13(2):134-40. doi: 10.2174/138920312800493205.
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.
无处不在且至关重要的 V-ATPase 是对抗不断升级的侵袭性真菌感染的有价值的化疗靶点。致病真菌需要最佳的 V-ATPase 功能来分泌毒力因子、诱导应激反应途径、菌丝形态以及 pH 值和其他阳离子的动态平衡，以便在宿主内成功存活并定植。本综述讨论了为什么 V-ATPase 活性的损伤会导致多药敏感性和毒力丧失。最近的证据表明，V-ATPase 是唑类抗真菌药物的一个新的下游靶标，唑类抗真菌药物抑制麦角固醇的生物合成。从液泡膜中耗尽麦角固醇导致酵母液泡逐渐碱化，V-ATPase 活性丧失和生长抑制，外源性麦角固醇喂养可挽救这种抑制。其他研究表明，鞘脂、磷脂和心磷脂在 V-ATPase 功能中起着关键作用。因此，直接抑制 V-ATPase 的药物，或通过调节膜环境间接抑制 V-ATPase 的药物，都可以显著影响真菌的生存能力和毒力。这些发现证明了对真菌特异性 V-ATPase 抑制剂或膜活性化合物进行系统筛选的合理性，这些抑制剂或化合物可用于抗真菌化疗。
