Exploring the chemistry of penicillin as a beta-lactamase-dependent prodrug.
The penam nucleus can be modified to behave as a beta-lactamase-dependent 'prodrug' by incorporation of a vinyl ester side chain at the 6-position. Enzyme-catalysed hydrolysis of the beta-lactam ring uncovers the thiazolidine-ring nitrogen as a nucleophile that drives a rapid intramolecular displacement on the side chain. Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generated a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of beta-lactamase enzyme in solution. Mechanistic details of the reaction pattern are documented and the scope and limitations of exploiting the structural modification are discussed.
Ruddle
Carol C
CC
Department of Chemical and Environmental Sciences, University of Limerick, National Technological Park, County Limerick, Ireland.
Smyth
Timothy P
TP
D000900:Anti-Bacterial Agents / Q000737:chemistry; D015394:Molecular Structure; D010406:Penicillins / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D010406:Penicillins; D011355:Prodrugs; D001618:beta-Lactamases