期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 63, 期 10, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00807-19
关键词
Aspergillus fumigatus; Saccharomyces cerevisiae; Sit1; antifungal drug; iron; siderophores
资金
- Austrian Science Fund (FWF) [I1346-B22, P29583, P39025-B26]
- Vical Inc.
- Austrian Science Fund (FWF) [P29583] Funding Source: Austrian Science Fund (FWF)
VL-2397 (previously termed ASP2397) is an antifungal, aluminum-chelating cyclic hexapeptide with a structure analogous to that of ferrichrome-type siderophores, whereby replacement of aluminum by iron was shown to decrease the antifungal activity of this compound. Here, we found that inactivation of an importer for ferrichrome-type siderophores, termed Sit1, renders Aspergillus fumigatus resistant to VL-2397. Moreover, expression of the endogenous sit! gene under the control of a xylose-inducible promoter (to uncouple sit! expression from iron repression) combined with C-terminal tagging with a fluorescent protein demonstrated localization of Sit1 in the plasma membrane and xylose-dependent VL-2397 susceptibility. This underlines that Sit1-mediated uptake is essential for VL-2397 susceptibility. Under xylose-induced sit1 expression, VL-2397 also retained antifungal activity after replacing aluminum with iron, which demonstrates that VL-2397 bears antifungal activity independent of cellular aluminum importation. Analysis of sit! expression indicated that the reduced antifungal activity of the iron-chelated VL-2397 is caused by downregulation of sit! expression by the imported iron. Furthermore, we demonstrate that defects in iron homeostatic mechanisms modulate the activity of VL-2397. In contrast to A. fumigatus and Candida glabrata, Saccharomyces cerevisiae displays intrinsic resistance to VL-2397 antifungal activity. However, expression of sit! from A. fumigatus, or its homologue from C. glabrata, resulted in susceptibility to VL-2397, which suggests that the intrinsic resistance of S. cerevisiae is based on lack of uptake and that A. fumigatus, C. glabrata, and S. cerevisiae share an intracellular target for VL-2397.
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