Aspergillus fumigatus Afssn3-Afssn8 Pair Reverse Regulates Azole Resistance by Conferring Extracellular Polysaccharide, Sphingolipid Pathway Intermediates, and Efflux Pumps to Biofilm
Aspergillus fumigatus Afssn3-Afssn8 Pair Reverse Regulates Azole Resistance by Conferring Extracellular Polysaccharide, Sphingolipid Pathway Intermediates, and Efflux Pumps to Biofilm
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烟曲霉 Afssn3-Afssn8 对通过赋予生物膜细胞外多糖、鞘脂通路中间体和外排泵来反向调节唑耐药性
DOI：
10.1128/aac.01978-17
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发表时间：
2018-03-01
影响因子：
4.9
通讯作者：
Zhong, Guowei
中科院分区：
文献类型：
--
作者：
Long, Nanbiao;Zeng, Liping;Zhong, Guowei
摘要抗真菌治疗常常是无效的，部分原因是生物膜的形成。在本研究中，我们采用正向和反向相结合的遗传策略，确定了构成CDK8-Cyclin对的细胞核定位的AfSn3及其伴侣AfSn8是烟曲霉对唑类抗药性所必需的。AfsSn3基因的缺失导致葡萄糖和氨基酸的吸收和利用增加。有趣的是，葡萄糖的吸收和利用加速了胞外多糖的形成，而氨基酸丝氨酸、苏氨酸和甘氨酸的利用增加了鞘磷脂途径中间产物的积累。此外，AFsSn3的缺失还诱导了外排泵蛋白的活性。这些因素表明，成熟的生物膜是ΔAfsSn3突变株烟曲霉菌抗唑的主要机制。总体而言，AfsSn3的丢失导致了细胞内和细胞外空间之间的两个“屏障”层，从而减少了药物对细胞的渗透。
ABSTRACT Antifungal treatment is often ineffectual, partly because of biofilm formation. In this study, by using a combined forward and reverse genetic strategy, we identified that nucleus-localized AfSsn3 and its partner AfSsn8, which constitute a Cdk8-cyclin pair, are required for azole resistance in Aspergillus fumigatus. Deletion of Afssn3 led to increased absorption and utilization of glucose and amino acids. Interestingly, absorption and utilization of glucose accelerated the extracellular polysaccharide formation, while utilization of the amino acids serine, threonine, and glycine increased sphingolipid pathway intermediate accumulation. In addition, the absence of Afssn3 induced the activity of the efflux pump proteins. These factors indicate the mature biofilm is responsible for the major mechanisms of A. fumigatus resistance to azoles in the ΔAfssn3 mutant. Collectively, the loss of Afssn3 led to two “barrier” layers between the intracellular and extracellular spaces, which consequently decreased drug penetration into the cell.