Selective inhibition of bacterial dihydroorotate dehydrogenases by thiadiazolidinediones

• Published in: Biochemical pharmacology Vol. 60; no. 3; pp. 339 - 342
• Main Authors: Marcinkeviciene, Jovita, Rogers, M.John, Kopcho, Lisa, Jiang, Wenjun, Wang, Kathy, Murphy, Dennis J, Lippy, Jonathan, Link, Steven, Chung, Thomas D.Y, Hobbs, Frank, Haque, Tasir, Trainor, George L, Slee, Andrew, Stern, Andrew M, Copeland, Robert A
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2000; Elsevier Science
• Subjects: Analytical, structural and metabolic biochemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; dihydroorotate dehydrogenase; Enterococcus faecalis; Enterococcus faecalis - drug effects; Enterococcus faecalis - enzymology; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Fundamental and applied biological sciences. Psychology; inhibition; Kinetics; Medical sciences; Microbial Sensitivity Tests; Oxidoreductases; Oxidoreductases - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors; Pharmacology. Drug treatments; Thiadiazoles - pharmacology; thiadiazolidinedione; time-dependent inactivation; Enterococcus faecalis; dihydroorotate dehydrogenase; inhibition; thiadiazolidinedione; Escherichia coli; time-dependent inactivation; Targeting; Enzyme; Enzyme inhibitor; Inactivation; Thiadiazole derivatives; Streptococcaceae; Antibiotic; Bacteria; Micrococcales; Oxidoreductases; Antibacterial agent; Dihydroorotate dehydrogenase; Enterobacteriaceae
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(00)00348-8

Dihydroorotate dehydrogenase is a critical enzyme of
de novo pyrimidine biosynthesis in prokaryotic and eukaryotic cells. Differences in the primary structure of the enzymes from Gram-positive and -negative bacteria and from mammals indicate significant structural divergence among these enzymes. We have identified a class of small molecules, the thiadiazolidinediones, that inhibit prototypical enzymes from Gram-positive and -negative bacteria, but are inactive against the human enzyme. The most potent compound in our collection functioned as a time-dependent irreversible inactivator of the bacterial enzymes with
k
inact/
K
i
values of 48 and 500 M
−1 sec
−1 for the enzymes from
Escherichia coli and
Enterococcus faecalis, respectively. The data presented here indicate that it is possible to inhibit prokaryotic dihydroorotate dehydrogenases selectively while sparing the mammalian enzyme. Thus, this enzyme may represent a valuable target for the development of novel antibiotic compounds.