Journal
CURRENT MEDICINAL CHEMISTRY
Volume 18, Issue 13, Pages 1909-1918Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/092986711795590129
Keywords
Antibacterial; Cryptosporidium parvum; guanine nucleotide biosynthesis; Helicobacter pylori; IMPDH; inosine 5 '-monophosphate dehydrogenase; select agents; Mycobacterium tuberculosis
Funding
- NIH-NIAID [U01 AI075466]
- University of Virginia [5T32 CA 009109]
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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.
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