Abstract
Campylobacter and Helicobacter species express a 6-amino-6-deoxyfutalosine N-ribosylhydrolase (HpMTAN) proposed to function in menaquinone synthesis. BuT-DADMe-ImmA is a 36 pM transition state analogue of HpMTAN, and the crystal structure of the enzyme-inhibitor complex reveals the mechanism of inhibition. BuT-DADMe-ImmA has a MIC(90) value of <8 ng/mL for Helicobacter pylori growth but does not cause growth arrest in other common clinical pathogens, thus demonstrating potential as an H. pylori-specific antibiotic.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / pharmacology
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Helicobacter Infections / drug therapy
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Helicobacter pylori / drug effects*
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Helicobacter pylori / enzymology*
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Humans
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Models, Molecular
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N-Glycosyl Hydrolases / antagonists & inhibitors*
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N-Glycosyl Hydrolases / metabolism
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology*
Substances
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4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)-immucillin A
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Pyrrolidines
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N-Glycosyl Hydrolases
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Adenine