Siccanin rediscovered as a species-selective succinate dehydrogenase inhibitor.
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 (IC(50), 0.9 microM), 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, P. 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.
Mogi
Tatsushi
T
Department of Biomedical Chemistry, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. tmogi@m.u-tokyo.ac.jp
Kawakami
Takuro
T
Arai
Hiroyuki
H
Igarashi
Yasuo
Y
Matsushita
Kazunobu
K
Mori
Mihoko
M
Shiomi
Kazuro
K
Omura
Satoshi
S
Harada
Shigeharu
S
Kita
Kiyoshi
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D048230:Corynebacterium glutamicum / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000201:enzymology; D007700:Kinetics; D051379:Mice; D008929:Mitochondria, Heart / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D016958:Pseudomonas putida / Q000201:enzymology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors; D051381:Rats; D013045:Species Specificity; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D019802:Succinic Acid / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism; D014966:Xanthenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D014966:Xanthenes; D014451:Ubiquinone; D019802:Succinic Acid; D010088:Oxidoreductases; C471971:malate dehydrogenase, FAD-dependent; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D011808:Quinone Reductases; C001795:siccanin