PDF(Pubmed)
Abstract：
More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.
摘要：
超过1000万人患有由致病真菌烟曲霉引起的肺部疾病。唑类抗真菌药物代表了大多数这些感染的一线治疗药物，但耐药性正在上升，因此,鉴定与唑类药物协同抑制的抗真菌靶点可以改善治疗效果.这里,我们在编码蛋白激酶的基因中产生了111个基因编码的烟曲霉无效突变体的文库，并显示激酶YakA功能的丧失导致对唑类药物的超敏反应和致病性降低。YakA是白色念珠菌Yak1的直向同源物，Yak1是一种参与调节应激反应转录调节因子的TOR信号通路激酶。我们表明，YakA已在烟曲霉中重新利用，以调节暴露于胁迫后中隔孔的阻塞。YakA功能的丧失降低了烟曲霉穿透固体培养基并在小鼠肺组织中生长的能力。我们还表明，1-乙氧基羰基-β-咔啉（1-ECBC），先前显示抑制白色念珠菌Yak1的化合物，可防止应激介导的间隔孢子阻断，并与唑类协同作用以抑制烟曲霉的生长。
