Tethered dimers as NAD synthetase inhibitors with antibacterial activity.

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Velu SE, Cristofoli WA, Garcia GJ, Brouillette CG, Pierson MC, Luan CH, DeLucas LJ, Brouillette WJ

Tethered dimers as NAD synthetase inhibitors with antibacterial activity.

J Med Chem. 2003 Jul 17;46(15):3371-81.

PubMed ID

12852767 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gentamicin	NH(3)-dependent NAD(+) synthetase	Protein	Bacillus subtilis (strain 168)	Unknown	Inhibitor	Details