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Journal of Biochemistry Advance Access published online on June 8, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp085
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Siccanin rediscovered as a species-selective succinate dehydrogenase inhibitor

Tatsushi Mogi1,*, Takuro Kawakami2, Hiroyuki Arai2, Yasuo Igarashi2, Kazunobu Matsushita3, Mihoko Mori4, Kazuro Shiomi4, Satoshi Omura4, Shigeharu Harada5 and Kiyoshi Kita1

1Department of Biomedical Chemistry, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033; 2Department of Biotechnology, the University of Tokyo, Bunkyo-ku, Tokyo 113-8657; 3Department of Biological Chemistry, Faculty of Agriculture, Yamaguchi University, Yamaguchi 753-8515; 4Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Tokyo 108-8641; 5Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan

*To whom correspondence should be addressed: Dr. Tatsushi Mogi: Tel: +81-3-5841-8202, Fax: +81-3-5841-3444, E-mail:tmogi{at}m.u-tokyo.ac.jp (T. Mogi).

Received May 20, 2009; Accepted May 20, 2009


  Abstract

To identify antibiotics targeting to respiratory enzymes, we carried out matrix screening of a structurally varied natural compound library with Pseudomonas aeruginosa membrane-bound respiratory enzymes. We identified a succinate dehydrogenase inhibitor, siccanin (IC50, 0.9 µM), which is a potent antibiotic against some pathogenic fungi like Trichophyton mentagrophytes and inhibits their mitochondrial succinate dehydrogenase. We found that siccanin was effective against enzymes from P. aeruginosa, Pseudomonas putida, rat and mouse mitochondria but ineffective or less effective against Escherichia coli, Corynebacterium glutamicum, and porcine mitochondria enzyme. Action mode was mixed-type for quinone-dependent activity and noncompetitive for succinate-dependent activity, indicating the proximity of the inhibitor-binding site to the quinone-binding site. Species-selective inhibition by siccanin is unique among succinate dehydrogenase inhibitors, and thus siccanin is a potential lead compound for new chemotherapeutics.

Key Words: Antibiotics, Complex II, Matrix screening, Respiratory chain, Siccanin, Succinate dehydrogenase


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