Sesquiterpene lactones are potent and irreversible inhibitors of the antibacterial target enzyme MurA.
We report the identification of the sesquiterpene lactones cnicin and cynaropicrin as potent, irreversible inhibitors of the bacterial enzyme MurA. They covalently bind to the thiol group of Cys115. Judging from the structure-activity relationships, we conclude that the unsaturated ester side chain of cynaropicrin and cnicin is of particular importance for the inhibition of MurA. These results provide evidence that MurA is a target protein of SLs with a probably high relevance for their known antibacterial effect.
Bachelier
Anke
A
Pharmazeutische und Medizinische Chemie, Saarland University, Germany.
Mayer
Ralf
R
Klein
Christian D
CD
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D010457:Peptidoglycan / Q000096:biosynthesis*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007783:Lactones; D010457:Peptidoglycan; D012717:Sesquiterpenes; C012849:cnicin; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase; C075687:cynaropicrin