Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis

We report the discovery of a class of pyrazole-based compounds that are pot ent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori b ut that do not inhibit the cognate enzymes from Gram-positive bacteria or h umans. In culture these compounds inhibit the growth of H, pylori selective ly, showing no effect on other Gram-negative or Gram-positive bacteria or h uman cell lines. These compounds represent the first examples of H, pylori- specific antibacterial agents. Cellular activity within this structural cla ss appears to be due to dihydroorotate dehydrogenase inhibition. Minor stru ctural changes that abrogate in vitro inhibition of the enzyme likewise eli minate cellular activity. Furthermore, the minimum inhibitory concentration s of these compounds increase upon addition of orotate to the culture mediu m in a concentration-dependent manner, consistent with dihydroorotate dehyd rogenase inhibition as the mechanism of cellular inhibition, The data prese nted here suggest that targeted inhibition of de novo pyrimidine biosynthes is may be a valuable mechanism for the development of antimicrobial agents selective for H, pylori.