Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases

Chem Biol. 2010 Oct 29;17(10):1084-91. doi: 10.1016/j.chembiol.2010.07.014.


The protozoan parasite Cryptosporidium parvum is a major cause of gastrointestinal disease; no effective drug therapy exists to treat this infection. Curiously, C. parvum IMPDH (CpIMPDH) is most closely related to prokaryotic IMPDHs, suggesting that the parasite obtained its IMPDH gene via horizontal transfer. We previously identified inhibitors of CpIMPDH that do not inhibit human IMPDHs. Here, we show that these compounds also inhibit IMPDHs from Helicobacter pylori, Borrelia burgdorferi, and Streptococcus pyogenes, but not from Escherichia coli. Residues Ala165 and Tyr358 comprise a structural motif that defines susceptible enzymes. Importantly, a second-generation CpIMPDH inhibitor has bacteriocidal activity on H. pylori but not E. coli. We propose that CpIMPDH-targeted inhibitors can be developed into a new class of antibiotics that will spare some commensal bacteria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Borrelia burgdorferi / drug effects
  • Borrelia burgdorferi / enzymology
  • Computer Simulation
  • Cryptosporidium parvum / enzymology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Helicobacter pylori / drug effects
  • Helicobacter pylori / enzymology
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors*
  • IMP Dehydrogenase / classification
  • IMP Dehydrogenase / metabolism
  • Kinetics
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Streptococcus pyogenes / drug effects
  • Streptococcus pyogenes / enzymology


  • Enzyme Inhibitors
  • Recombinant Proteins
  • IMP Dehydrogenase