Inhibition of Escherichia coli growth and diaminopimelic acid epimerase by 3-chlorodiaminopimelic acid.
The diaminopimelic acid (DAP) analog, 3-chloro-DAP, was synthesized and tested as the racemic acid for antibacterial activity and for inhibition of DAP epimerase. 3-Chloro-DAP was a potent inhibitor of DAP epimerase purified from Escherichia coli (Ki = 200 nM), and it is argued that 3-chloro-DAP is converted to a tight-binding transition state analog at the active site of this enzyme. Furthermore, 3-chloro-DAP inhibited growth of two E. coli mutants. In one of the mutants known for supersusceptibility to beta-lactams, inhibition was not seen until the mid-log phase of growth, while in the other mutant, a DAP auxotroph, inhibition occurred much earlier. Growth inhibition was reversed by DAP in both strains. In the auxotroph, the reversal was specific for meso-DAP, indicating that DAP epimerase was the target for 3-chloro-DAP. Thus we suggest a novel mechanism of bacterial growth inhibition which depends on DAP epimerase inhibition by a DAP analog.
Baumann
R J
RJ
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Bohme
E H
EH
Wiseman
J S
JS
Vaal
M
M
Nichols
J S
JS
D000591:Amino Acid Isomerases; D000599:Amino Acids, Diamino / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D007535:Isomerases / Q000037:antagonists & inhibitors*; D009154:Mutation; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*
D000599:Amino Acids, Diamino; C057526:3-chlorodiaminopimelic acid; D003960:Diaminopimelic Acid; D007535:Isomerases; D019998:Racemases and Epimerases; D000591:Amino Acid Isomerases; C042032:diaminopimelate epimerase