Acta Pharmacologica Sinica (2009) 30: 1709–1716; doi: 10.1038/aps.2009.157; published online 16 Nov 2009

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.

Keywords: Candida albicans; sterol C-14 reducase; ergosterol; 2-amino-nonyl-6-methoxyl-tetralin muriate