Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis.
We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori but that do not inhibit the cognate enzymes from Gram-positive bacteria or humans. In culture these compounds inhibit the growth of H. pylori selectively, showing no effect on other Gram-negative or Gram-positive bacteria or human cell lines. These compounds represent the first examples of H. pylori-specific antibacterial agents. Cellular activity within this structural class appears to be due to dihydroorotate dehydrogenase inhibition. Minor structural changes that abrogate in vitro inhibition of the enzyme likewise eliminate cellular activity. Furthermore, the minimum inhibitory concentrations of these compounds increase upon addition of orotate to the culture medium in a concentration-dependent manner, consistent with dihydroorotate dehydrogenase inhibition as the mechanism of cellular inhibition. The data presented here suggest that targeted inhibition of de novo pyrimidine biosynthesis may be a valuable mechanism for the development of antimicrobial agents selective for H. pylori.
Department of Chemical Enzymology, the Department of Chemical and Physical Sciences, and the Antimicrobials Group, DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA.
R A
RA
Copeland
J
J
Marcinkeviciene
T S
TS
Haque
L M
LM
Kopcho
W
W
Jiang
K
K
Wang
L D
LD
Ecret
C
C
Sizemore
K A
KA
Amsler
L
L
Foster
S
S
Tadesse
A P
AP
Combs
A M
AM
Stern
G L
GL
Trainor
A
A
Slee
M J
MJ
Rogers
F
F
Hobbs
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011743:Pyrimidines / Q000096:biosynthesis*; D014451:Ubiquinone / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014451:Ubiquinone; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors