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Rugulactone and its Analogues Exert Antibacterial Effects through Multiple Mechanisms Including Inhibition of Thiamine Biosynthesis
Author(s) -
Nodwell Matthew B.,
Menz Helge,
Kirsch Stefan F.,
Sieber Stephan A.
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201200265
Subject(s) - bacteria , thiamine , biosynthesis , biochemistry , listeria monocytogenes , pathogenic bacteria , staphylococcus aureus , listeria , chemistry , microbiology and biotechnology , biology , enzyme , genetics
Rugulactone is a dihydro‐α‐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.