Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.

三唑类是应用最广泛的一类抗真菌药物，可抑制麦角甾醇的生物合成，而麦角甾醇是真菌质膜的重要组成部分。抑制由甾醇 C-24 甲基转移酶 Erg6 催化的单独麦角甾醇生物合成步骤可降低病原酵母菌的毒力，但其对烟曲霉等丝状真菌病原体的影响仍有待探索。在这里，我们证明脂滴相关酶 Erg6 对于烟曲霉和其他曲霉属物种（包括A. lentulus 、 A. terreus和 A. nidulans）的生存至关重要。 erg6的下调会导致菌丝顶端延伸所需的富含甾醇的膜结构域的损失，以及与三唑药物靶点 Cyp51A/Cyp51B 上游的 Erg6 酶功能一致的甾醇谱的改变。出乎意料的是， erg6抑制菌株表现出对麦角甾醇活性三唑和多烯抗真菌剂的野生型敏感性。最后，我们发现， erg6抑制可显着降低侵袭性曲霉病小鼠模型的死亡率。结合最近的研究，我们的工作支持 Erg6 作为潜在的泛真菌药物靶点。