Abstract
Aim:
To investigate the action mechanism of a novel chemical structural aminotetralin derivate, 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), against Candida albicans (C albicans) in the ergosterol biosynthetic pathway.
Methods:
Antifungal susceptibility test of 10b was carried out using broth microdilution method, the action mechanism of 10b against C albicans was investigated by GC-MS spectrometry and real-time RT-PCR assay, and cytotoxicity of 10b in vitro was assessed by MTS/PMS reduction assay.
Results:
10b reduced the ergosterol content markedly, and the 50% ergosterol content inhibitory concentration (ECIC50 value) was 0.08 μg/mL. Although the sterol composition of 10b-grown cells was completely identical with that of erg24 strain, the content of ergosta-8,14,22-trienol in 10b-grown cells was much higher than that in erg24 strain. Real-time RT-PCR assay revealed a global upregulation of sterol metabolism genes. In addition, the 50% inhibitory concentration (IC50 value) of 10b was 11.30 μg/mL for murine embryonic fibroblasts and 35.70 μg/mL for human normal liver cells.
Conclusion:
10b possessed a mode of action different from that of azoles and morpholines, whose targets were sterol C-14 reductase (encoded by ERG24 gene) and sterol C-5 desaturase (encoded by ERG3) related enzyme. Although 10b seemed to reduce MTS/PMS reduction in a dose dependent manner, IC50 value for mammalian cells was much higher than 50% minimum inhibitory concentration (MIC50) value for C albicans. This indicates that the formulation is preliminarily safe and warrants further study for possible human applications.
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Acknowledgements
Project was supported by the National Natural Science Foundation of China (No 30672626 and 30572257).
We thank Dr Joseph HEITMAN for kindly providing the isolate C albicans strain BWP17 and NJ52-1 and Dr William A FONZI for kindly offering the isolate C albicans SC5314 in this study.
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Liang, Rm., Cao, Yb., Fan, Kh. et al. 2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway. Acta Pharmacol Sin 30, 1709–1716 (2009). https://doi.org/10.1038/aps.2009.157
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DOI: https://doi.org/10.1038/aps.2009.157
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