源于农用三唑类化合物使用的农田土壤中烟曲霉抗药性相关cyp51A基因突变

Invasive aspergillosis caused by infection of Aspergillus fumigatus is a main lethal factor for the immunocompromised patients. Triazoles are the mainstay of therapy in infections with Aspergillus fumigatus. However, azole resistance is emerging in Aspergillus fumigatus isolates and becomes a new challenge in the management of invasive aspergillosis. The main resistance mechanism is a point mutation of cyp51A, the gene encoding the target enzyme of triazole antifungal drugs. To find the relationship between the emergency of resistant A. fumigates with mutation of cyp51A and the applications of triazoles in agriculture, the possible mutations of cyp51A in isolates of A. fumigates from agricultural fields and in soil samples successively received triazoles will be investigated in this study. The fitness of resistant A. fumigates in soil will also be studied to explore its persistence in soil. The results of this study will be helpful for the understanding the sources of the resistance in A. fumigates and finding the ways for the management of the resistance.

烟曲霉引起的侵袭性曲霉病是免疫抑制人群主要致死因子，其治疗主要依赖于三唑类药物。然而，烟曲霉普遍对三唑类药物存在耐药性和抗药性，成为侵袭性曲霉病治疗的巨大挑战。揭示烟曲霉抗药性的来源有助于科学预防抗性形成并保障侵袭性曲霉病的控制。三唑类药物靶标酶基因cyp51A突变是烟曲霉抗药性主要成因。本项目针对三唑类药物结构类似的农用三唑类化合物使用诱导农田土壤中烟曲霉cyp51A突变并产生抗药性问题，研究：1）农田土壤中烟曲霉抗药性相关cyp51A突变及其普遍性；2）三唑类农药诱导烟曲霉产生的抗药性相关cyp51A突变；3）分析抗性烟曲霉在土壤中的适合度，明确抗性烟曲霉在土壤中生存、繁殖的持续性。项目研究将回答"农用三唑类化合物使用导致农田土壤中烟曲霉产生突变并形成抗药性"这一科学问题，从而从农药使用角度提出预防烟曲霉抗药性的途径，为烟曲霉抗药性的认识和预防提供新思路。

烟曲霉引起的侵袭性曲霉病是免疫抑制人群主要致死因子，其治疗主要依赖于三唑类药物。然而，烟曲霉普遍对三唑类药物存在耐药性和抗药性，成为侵袭性曲霉病治疗的巨大挑战。揭示烟曲霉抗药性的来源有助于科学预防抗性形成并保障侵袭性曲霉病的控制。项目针对三唑类药物结构类似的农用三唑类化合物使用诱导农田土壤中烟曲霉cyp51A突变并产生抗药性问题，研究了：1）农田土壤中烟曲霉抗药性相关cyp51A突变及其普遍性；2）三唑类农药使用诱导下烟曲霉抗药性相关cyp51A突变；3）抗性烟曲霉在土壤中适合度。试验结果表明：1）苯醚甲环唑、丙环唑、戊唑醇等三唑类杀菌剂在土壤中的残留胁迫可诱导烟曲霉产生对三唑类医药的抗药性；2）土壤中三唑类杀菌剂诱导产生的烟曲霉抗药性机理在于cyp51A突变（TR46/Y121F/T289A、F46Y\M172V\N248T\D255E\E427K、G138S、TR34/L98H/S297T/T495I）和外排基因（AtrF、AfuMDR1 、AfuMDR2、 AfuMDR3和AfuMDR4）过表达；3）cyp51A突变相关烟曲霉抗药性可稳定遗传，非cyp51A突变抗性烟曲霉易于回复敏感；4）土壤中抗药性烟曲霉丰度未上升，适合度基本不变。