2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway.
OBJECTIVE
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 (ECIC(50) value) was 0.08 microg/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 (IC(50) value) of 10b was 11.30 microg/mL for murine embryonic fibroblasts and 35.70 microg/mL for human normal liver cells.


CONCLUSIONS
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, IC(50) value for mammalian cells was much higher than 50% minimum inhibitory concentration (MIC(50)) value for C albicans. This indicates that the formulation is preliminarily safe and warrants further study for possible human applications.
Liang
Rong-mei
RM
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
Cao
Yong-bing
YB
Fan
Kai-hua
KH
Xu
Yi
Y
Gao
Ping-hui
PH
Zhou
You-jun
YJ
Dai
Bao-di
BD
Tan
Yong-hong
YH
Wang
Shi-hua
SH
Tang
Hui
H
Liu
Hong-tao
HT
Jiang
Yuan-ying
YY
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D041702:BALB 3T3 Cells / Q000187:drug effects; D053898:Biosynthetic Pathways; D002176:Candida albicans / Q000187:drug effects*; D004875:Ergosterol / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D015854:Up-Regulation
C550315:2-amino-nonyl-6-methoxyl-tetralin muriate; D000935:Antifungal Agents; D001393:Azoles; D013261:Sterols; D013764:Tetrahydronaphthalenes; D010088:Oxidoreductases; C039306:sterol delta-5 desaturase; C022672:delta(14)-sterol reductase; D004875:Ergosterol