The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors
L. Hedstrom, G. Liechti, J. B. Goldberg and D. R. Gollapalli
Affiliation: Brandeis University, Departments of Chemistry, Waltham, MA 02454-9110, USA.
Inosine 5-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of guanosine 5-monophosphate (GMP) biosynthesis, and thus regulates the guanine nucleotide pool, which in turn governs proliferation. Human IMPDHs are validated targets for immunosuppressive, antiviral and anticancer drugs, but as yet microbial IMPDHs have not been exploited in antimicrobial chemotherapy. Selective inhibitors of IMPDH from Cryptosporidium parvum have recently been discovered that display anti-parasitic activity in cell culture models of infection. X-ray crystal structure and mutagenesis experiments identified the structural features that determine inhibitor susceptibility. These features are found in IMPDHs from a wide variety of pathogenic bacteria, including select agents and multiply drug resistant strains. A second generation inhibitor displays antibacterial activity against Helicobacter pylori, demonstrating the antibiotic potential of IMPDH inhibitors.
Keywords: Antibacterial, Cryptosporidium parvum, guanine nucleotide, biosynthesis, Helicobacter pylori, IMPDH, inosine 5'- monophosphate dehydrogenase, select agents, Mycobacterium tuberculosis
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