Rugulactone and its Analogues Exert Antibacterial Effects through Multiple Mechanisms Including Inhibition of Thiamine Biosynthesis

Rugulactone is a dihydro-a-pyrone isolated from the plant Cryptocarya rugulosa in 2009. It has been reported to display IkB kinase (IKK) inhibitory activity, as well as antibiotic activity in several strains of pathogenic bacteria. However, its biological targets and mode of action in bacteria have not yet been explored. Here we present enantioselective syntheses of rugulactone and of some corresponding activity-based protein profiling (ABPP) probes. We found that the ABPP probes in this study are more potent than rugulactone against Staphyloccocus aureus NCTC 8325, S. aureus Mu50, Listeria welshimeri SLCC 5334 and Listeria monocytogenes EGD-e, and that molecules of this class probably exert their antibacterial effect through a combination of targets. These targets include covalent inhibition of 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMPP) kinase (ThiD), which is an essential component of the thiamine biosynthesis pathway in bacteria. This represents the first example of a small-molecule inhibitor of ThiD.     «

Rugulactone is a dihydro-a-pyrone isolated from the plant Cryptocarya rugulosa in 2009. It has been reported to display IkB kinase (IKK) inhibitory activity, as well as antibiotic activity in several strains of pathogenic bacteria. However, its biological targets and mode of action in bacteria have not yet been explored. Here we present enantioselective syntheses of rugulactone and of some corresponding activity-based protein profiling (ABPP) probes. We found that the ABPP probes in this study a...     »

ISI Document Delivery No.: 967XQ Times Cited: 2 Cited Reference Count: 43 Nodwell, Matthew B. Menz, Helge Kirsch, Stefan F. Sieber, Stephan A. Deutsche Forschungsgemeinschaft [SFB749, FOR1406]; ERC; Center for Integrated Protein Science, Munich (CIPSM); Alexander von Humboldt foundation We thank Mona Wolf for excellent scientific support and Max Pitcheider for the E. coli clones. We also thank Tadhg Begley for the kind gift of HMP. S. A. S. was supported by the Deutsche Forschungsgemeinschaft, SFB749, FOR1406, an ERC starting grant and the Center for Integrated Protein Science, Munich (CIPSM). M.B.N. thanks the Alexander von Humboldt foundation for financial support. 2 Wiley-v c h verlag gmbh Weinheim     «

ISI Document Delivery No.: 967XQ Times Cited: 2 Cited Reference Count: 43 Nodwell, Matthew B. Menz, Helge Kirsch, Stefan F. Sieber, Stephan A. Deutsche Forschungsgemeinschaft [SFB749, FOR1406]; ERC; Center for Integrated Protein Science, Munich (CIPSM); Alexander von Humboldt foundation We thank Mona Wolf for excellent scientific support and Max Pitcheider for the E. coli clones. We also thank Tadhg Begley for the kind gift of HMP. S. A. S. was supported by the Deutsche Forschungsgemeinschaft...     »