title: Tethered dimers as NAD synthetase inhibitors with antibacterial activity.
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.
authors.affiliation: Center for Biophysical Sciences and Engineering, 1025 18th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294-4400, USA.
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.forename: Walter A
authors.initials: WA
authors.lastname: Cristofoli
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Garcia
authors.forename: Christie G
authors.initials: CG
authors.lastname: Brouillette
authors.forename: Milton C
authors.initials: MC
authors.lastname: Pierson
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: DeLucas
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D019281:Dimerization; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D009539:Nicotinic Acids; D010648:Phenylacetates; D019732:Amide Synthases; C038479:NAD+ synthase