title: Inhibition of bacterial undecaprenyl pyrophosphate synthase by small fungal molecules.
abstract: Viridicatumtoxin and spirohexaline, small fungal molecules with a tetracyclic scaffold and an additional spirobicyclic ring in common, were found to inhibit bacterial undecaprenyl pyrophosphate (UPP) synthase with IC50values of 4 and 9 μm, respectively. These molecules showed weak inhibitory activity against catalytically related enzymes such as bacterial octaprenyl pyrophosphate synthase and yeast dehydrodolichyl pyrophosphate synthase, indicating that the compounds preferentially inhibit UPP synthase. They showed antimicrobial activity, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, molecular modeling strongly suggested that the hydrophobic spirobicyclic ring of viridicatumtoxin interacts with three hydrophobic clefts of the active site in MRSA UPP synthase.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Inokoshi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Komada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Katsuichiro
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Umeyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009183:Mycotoxins / Q000494:pharmacology*; D010407:Penicillium / Q000737:chemistry; D013141:Spiro Compounds / Q000494:pharmacology*; D054457:Tissue Scaffolds
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009183:Mycotoxins; D013141:Spiro Compounds; C573901:spirohexaline; D019883:Alkyl and Aryl Transferases; C048987:octaprenyl pyrophosphate synthetase; C023266:undecaprenyl pyrophosphate synthetase; C042170:viridicatumtoxin