Abstract
The solution-phase parallel synthesis of tethered dimers was employed to identify lead inhibitors of bacterial NAD synthetase. Active dimers contained two aromatic end groups joined by a polymethylene linker, with one end group containing a permanent positive charge. Effective inhibitors of NAD synthetase also inhibited the growth of Gram-positive (but not Gram-negative) bacteria, including antibiotic-resistant strains. The desmethyl precursors of active inhibitors lacked a permanent positive charge and were inactive as either enzyme inhibitors or antibacterial agents. Similarly, a close structural analogue of the most active inhibitors contained two additional ether oxygens in the tether and was inactive in both assays. These results are consistent with the premise that NAD synthetase inhibition is responsible for the antibacterial actions and support further studies on NAD synthetase as a new target for antibacterial agents.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amide Synthases / antagonists & inhibitors*
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Amide Synthases / chemistry
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Bacillus subtilis / chemistry
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Dimerization
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Drug Resistance, Bacterial
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Gram-Positive Bacteria / drug effects
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Models, Molecular
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Nicotinic Acids / chemical synthesis
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Nicotinic Acids / chemistry
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Nicotinic Acids / pharmacology
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Phenylacetates / chemical synthesis
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Phenylacetates / chemistry
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Phenylacetates / pharmacology
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Indoles
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Nicotinic Acids
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Phenylacetates
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Amide Synthases
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NAD+ synthase