Microbial samples, including our library of known microbial compounds (ca. 300) and microbial culture broths (ca. 9000), were screened for small molecules affecting the phenotype of Caenorhabditis elegans. As a result, seven known compounds were found to induce phenotypic abnormality of C. elegans. Staurosporine exhibited morphological defects in the vulva and tail of C. elegans, avermectin B1a exhibited hatching inhibition of starting eggs on day 1 at 25-100 µM and growth inhibition at 0.01-12.5 µM, siccanin and antimycin A inhibited the growth of C. elegans, and fluorouracil inhibited hatching of eggs newly spawned by adult C. elegans. Toromycin induced morphological defects in the intestine. 5-(4-Methoxyphenyl)-oxazole, isolated as a fungal metabolite for the first time, inhibited the hatching of eggs newly spawned by adult C. elegans.

01 Sep 2009·Journal of BiochemistryQ4 · BIOLOGY

Siccanin Rediscovered as a Species-Selective Succinate Dehydrogenase Inhibitor

Q4 · BIOLOGY

Article

Author: Mori, Mihoko ; Kita, Kiyoshi ; Matsushita, Kazunobu ; Kawakami, Takuro ; Omura, Satoshi ; Harada, Shigeharu ; Arai, Hiroyuki ; Igarashi, Yasuo ; Shiomi, Kazuro ; Mogi, Tatsushi

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.

16 Jan 2006·Angewandte Chemie International EditionQ1 · CHEMISTRY

Antibiotics and Much More

Q1 · CHEMISTRY

Review

Author: Krohn, Karsten

The synthesis of biologically active natural and synthetic compounds is without doubt a topical field of activity. A forum for the exchange of the most recent results in this area was provided by the 9th International Conference on the Chemistry of Antibiotics and Other Bioactive Compounds (ICCA-9), organized by St$phane Quideau (University of Bordeaux), which took place in Arcachon (France) during September 25–29, 2005. A feature of this series of conferences is the participation of researchers from both academia and industry: This year, industrial chemists represented about a third of the 140 participants. The focus of the conference was bioactive compounds—not just antibiotics, which were discussed in only about a third of the lectures. Nevertheless, the increasingly observed resistance of bacteria to antibiotics has lent an urgency to research into antibiotics. Who better to introduce this topic than C. Walsh (Harvard Medical School), who recently appeared as the editor of a whole volume of Chemical Reviews on this theme? Indeed, the theme of the development of resistance stood at the center of his plenary lecture “Antibiotics: Past, Present, Future”. On the basis of the most recent results on the mechanisms of action of antibiotics, Walsh stated that the development of resistance is unavoidable and a further rapid proliferation of multidrug resistance has to be expected. Even today, about 30% of enterococci are resistant towards vancomycin, leading to a mortality rate of around 25% in infected, immunedeficient patients. Added to this, the large gap in the development of new antibiotics that after almost 40 years was interrupted with the oxazolidinones (2000) and daptomycin (2003) appears critical. The upshot of his lecture was the requirement for increased research efforts in this area to find new targets, new molecules, and a greater level of success in the discovery of antibiotics that are active against resistant pathogens. Closely associated with the synthesis of natural products is the continued development of synthetic methods. A prime example of this was given at the beginning by J. Mulzer (University of Vienna, Austria), who presented the most recent results on two difficult problems: control of the E/Z geometry of the double bond (e.g. in epothilones) and stereocontrol of radical processes in conjunction with isoprostane syntheses. As an example, the metathesis reaction in the Danishefsky epothilone synthesis gives only a 1:1 ratio of the E/Z isomers; however, the selectivity is improved by a new concept that involves the fragmentation of b-hydroxy esters (simultaneous elimination of CO2 and HOR) starting from cyclic precursors (Scheme 1). The control of stereochemistry and the development of new synthetic strategies was discussed in the plenary lecture by B. M. Trost (Stanford University). The “taming” of radical cyclizations for a stereoselective outcome was introduced with the example of the synthesis of siccanin. The efficiency and the diversity of substrates controlled by palladiumor ruthenium-catalyzed allylations with the assistance of C2-symmetric amidophosphines 1a, 1b, and 2 was demonstrated impressively with many examples of natural product syntheses.

100 Deals associated with Siccanin

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KEGG	Wiki	ATC	Drug Bank
D01257	-	D01A	-

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Skin Diseases, Infectious	-	-	-

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