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Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases

Deviprasad R Gollapalli1, Iain S Macpherson, George Liechti

  • 1Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454-9110, USA.

Chemistry & Biology
|November 2, 2010
PubMed

Insights

New drug candidates targeting Cryptosporidium parvum inosine monophosphate dehydrogenase (CpIMPDH) show promise as novel antibiotics. These inhibitors are effective against various bacterial IMPDHs, sparing beneficial gut bacteria.

Area of Science:

  • Parasitology
  • Microbiology
  • Drug Discovery

Background:

  • Cryptosporidium parvum causes significant gastrointestinal illness with no effective treatments.
  • CpIMPDH exhibits close homology to prokaryotic IMPDHs, suggesting horizontal gene transfer.
  • Existing CpIMPDH inhibitors do not affect human IMPDH, indicating target specificity.

Purpose of the Study:

  • To investigate the potential of CpIMPDH inhibitors as broad-spectrum antibacterial agents.
  • To identify structural features of IMPDH enzymes conferring susceptibility to inhibitors.
  • To evaluate the therapeutic potential of second-generation inhibitors against specific bacterial pathogens.

Main Methods:

  • Enzyme inhibition assays using CpIMPDH and IMPDH from various bacterial species (H. pylori, B. burgdorferi, S. pyogenes, E. coli).
  • Structural analysis to identify key residues (Ala165, Tyr358) in susceptible IMPDH enzymes.
  • Bactericidal activity assays of a second-generation CpIMPDH inhibitor against H. pylori and E. coli.

Main Results:

  • CpIMPDH inhibitors demonstrated activity against IMPDH from H. pylori, B. burgdorferi, and S. pyogenes, but not E. coli.
  • A conserved structural motif (Ala165, Tyr358) was identified as critical for enzyme susceptibility.
  • A second-generation inhibitor exhibited bactericidal effects on H. pylori without harming E. coli.

Conclusions:

  • CpIMPDH-targeted inhibitors represent a promising new class of antibiotics.
  • These compounds show selective activity against pathogenic bacteria, potentially sparing commensal flora.
  • Further development could lead to novel therapeutic strategies for parasitic and bacterial infections.

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