A Vma13-targeted thiadiazole-succinimide disrupts V-ATPase dependent arginine-polyamine homeostasis to block Candida albicans escape from macrophages

ETSI, a Vma13-targeted thiadiazole-succinimide, blocks Candida albicans escape from macrophages by disrupting V-ATPase–dependent arginine–polyamine homeostasis.

• Why it matters: Macrophage phagosomes provide arginine-rich conditions that support polyamine synthesis, phagosomal alkalinization, yeast-to-hypha switching, and escape, yet antifungals that specifically block this escape are limited.
• What they did: ETSI shows minimal direct growth inhibition without arginine but strong activity in arginine-rich, macrophage-like microenvironments; it inhibits vacuolar Vma13, dissipating V-ATPase proton gradients and causing cytoplasmic H+ retention.
• The result: The resulting cytoplasmic H+ traps ammonia and prevents its release, while impaired vacuolar sequestration drives toxic buildup of arginine and polyamine metabolites, suppressing alkalinization, retaining yeast form, and blocking macrophage escape.

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