Impairing fluoride export of Aspergillus fumigatus mitigates its voriconazole resistance
Impairing fluoride export of Aspergillus fumigatus mitigates its voriconazole resistance
复制标题
DOI：
10.1016/j.ijantimicag.2019.02.003
复制
发表时间：
2019-05-01
影响因子：
10.8
通讯作者：
Krappmann, Sven
中科院分区：
文献类型：
--
作者：
Binder, Jasmin;Held, Juergen;Krappmann, Sven
真菌已经进化出特定的输出活动来平衡有毒离子氟化物的细胞内水平，而一线抗真菌药伏立康唑含有氟。本研究旨在探讨是否受损的氟输出可能会导致人类致病性霉菌烟曲霉对这种抗真菌化合物的敏感性改变。A中假定的氟化物输出者的功能表征。在唑类耐药性的背景下，通过产生缺失菌株来进行烟曲霉的测定，所述缺失菌株被评估其对氟化物和伏立康唑的耐药性。FexA是A.烟曲霉素似乎是组成型表达的，靶向其编码基因导致对这种卤化物的敏感性显著增加。氟输出受损与耐唑fexA Delta菌株易感性增加相关这些结果表明，fexA编码的基因产物是A.烟曲霉，伏立康唑作为氟化物的来源。然而，这些数据不支持基于氟毒性的伏立康唑的应用。(C)2019 Elsevier B.V.和国际化疗学会。All rights reserved.
Fungi have evolved specific export activities to balance intracellular levels of the toxic ion fluoride, while the first-line antimycotic voriconazole contains fluorine. This study aimed to explore whether impaired fluoride export might result in altered susceptibilities of the human pathogenic mould Aspergillus fumigatus towards this antifungal compound. Functional characterization of the putative fluoride exporter in A. fumigatus was performed in the context of azole resistance by generating deletion strains that were assessed for their resistance against fluoride and voriconazole. The FexA fluoride exporter of A. fumigatus appears to be expressed constitutively, and targeting its encoding gene results in significantly increased sensitivity towards this halide. Impaired fluoride export correlates with increased susceptibility of an azole-resistant fexA Delta strain. These results demonstrate that the fexA-encoded gene product is the major fluoride export activity of A. fumigatus, and that voriconazole serves as a source of fluoride. However, these data do not support the application of voriconazole based on fluoride toxicity. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.