Graduate Program in Pharmaceutical Sciences, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
Nat Commun. 2024 May 20;15(1):4261. doi: 10.1038/s41467-024-48767-3.
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.
三氮唑类是应用最广泛的一类抗真菌药物，其作用机制是抑制麦角甾醇的生物合成，而麦角甾醇是真菌细胞膜的重要组成部分。另一种固醇 C-24 甲基转移酶 Erg6 催化的固醇生物合成步骤的抑制降低了致病性酵母的毒力，但它对烟曲霉等丝状真菌病原体的影响仍未被探索。在这里，我们表明与脂滴相关的酶 Erg6 对烟曲霉和其他曲霉属物种（包括构巢曲霉、土曲霉和粗糙脉孢菌）的生存是必需的。erg6 的下调导致富含固醇的膜结构域缺失，这些膜结构域对于菌丝顶端延伸是必需的，同时固醇图谱也发生改变，这与 Erg6 酶在三唑类药物靶点 Cyp51A/Cyp51B 的上游发挥作用一致。出乎意料的是，erg6 受抑制的菌株对麦角甾醇活性的三唑类和多烯类抗真菌药物表现出野生型敏感性。最后，我们表明 erg6 抑制可显著降低侵袭性曲霉病的小鼠模型中的死亡率。结合最近的研究，我们的工作支持 Erg6 作为一个潜在的泛真菌药物靶点。
