Analogs of diaminopimelic acid as inhibitors of meso-diaminopimelate dehydrogenase and LL-diaminopimelate epimerase.
Analogs 1-8 of diaminopimelic acid (DAP) were synthesized and tested for inhibition of purified meso-DAP D-dehydrogenase from Bacillus sphaericus and of LL-DAP epimerase from Escherichia coli. The dehydrogenase was assayed by monitoring NADPH formation spectrophotometrically at 340 nm. N-Hydroxy DAP 4, N-amino DAP 5, and 4-methylene DAP 6 are substrates of the dehydrogenase with relative rates exceeding those of the meso isomers of the thia analogs 1ab, 2ab, and 3ab. DAP epimerase was assayed by coupling the epimerization of LL-DAP to DL-DAP (Km = 0.26 mM) with the dehydrogenase-catalyzed oxidation of DL-DAP by NADP. Lanthionine isomers 1ab and 1c were stronger inhibitors of the epimerase (Ki = 0.18 mM, Ki' = 0.67 mM, and Ki = 0.42 mM, respectively) than the corresponding meso-sulfoxide 2ab or the meso-sulfone 3ab. Other isomers of 2 and 3, as well as compounds 7 and 8, showed no epimerase inhibition. N-Hydroxy DAP 4 was the most potent competitive inhibitor (Ki = 0.0056 mM) of the epimerase, whereas N-amino DAP 5 is weaker (Ki = 2.9 mM) and 4-methylene DAP 6 is a noncompetitive inhibitor (Ki' = 0.95 mM). Although none of the analogs tested showed time-dependent inactivation of either enzyme, compounds 4, 5, 6, and 7 display substantial antibacterial activities. Possible mechanisms of epimerase inhibition and significance of the DAP pathway as a target for antibiotics are discussed.
D000591:Amino Acid Isomerases; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000599:Amino Acids, Diamino; D000900:Anti-Bacterial Agents; D001407:Bacillus / Q000201:enzymology*; D001419:Bacteria / Q000187:drug effects; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives; D004926:Escherichia coli / Q000201:enzymology*; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009249:NADP / Q000378:metabolism; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*; D013053:Spectrophotometry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013455:Sulfur
D000599:Amino Acids, Diamino; D000900:Anti-Bacterial Agents; D009249:NADP; D003960:Diaminopimelic Acid; D013455:Sulfur; D000594:Amino Acid Oxidoreductases; C020032:diaminopimelate dehydrogenase; D007535:Isomerases; D019998:Racemases and Epimerases; D000591:Amino Acid Isomerases; C042032:diaminopimelate epimerase