Velu Sadanandan E, Cristofoli Walter A, Garcia Gabriel J, Brouillette Christie G, Pierson Milton C, Luan Chi-Hao, DeLucas Lawrence J, Brouillette Wayne J
Center for Biophysical Sciences and Engineering, 1025 18th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294-4400, USA.
J Med Chem. 2003 Jul 17;46(15):3371-81. doi: 10.1021/jm030003x.
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.
