The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

Authors: Hedstrom, L.; Liechti, G.; B. Goldberg, J.; R. Gollapalli, D.

Source: Current Medicinal Chemistry, Volume 18, Number 13, May 2011 , pp. 1909-1918(10)

Publisher: Bentham Science Publishers

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Abstract:

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

Document Type: Research article

DOI: http://dx.doi.org/10.2174/092986711795590129

Publication date: 2011-05-01

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Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.