Siccanin Rediscovered as a Species-Selective Succinate Dehydrogenase Inhibitor

• DOI: 10.1093/jb/mvp085
• Publication Date: 2009-06-09T00:34:50Z
• Authors: T. Mogi; T. Kawakami; H. Arai; Y. Igarashi; K. Matsushita; M. Mori; K. Shiomi; S. Omura; S. Harada; K. Kita
• Keywords: 0303 health sciences; Binding Sites; Pseudomonas putida; Electron Transport Complex II; Drug Evaluation, Preclinical; Mitochondria, Liver; Intracellular Membranes; Mitochondria, Heart; Anti-Bacterial Agents; Rats; 3. Good health; Corynebacterium glutamicum; Inhibitory Concentration 50; Kinetics; Mice; 03 medical and health sciences; Species Specificity; Pseudomonas aeruginosa; Escherichia coli; Animals; Enzyme Inhibitors; Quinone Reductases; Oxidoreductases

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.