Title of article :
Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes Original Research Article
Author/Authors :
Karen T. Welch، نويسنده , , Kristopher G. Virga، نويسنده , , Neil A. Whittemore، نويسنده , , Can ?zen، نويسنده , , Edward Wright، نويسنده , , Cynthia L. Brown، نويسنده , , Richard E. Lee and Stephen W. White، نويسنده , , Engin H. Serpersu، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2005
Pages :
12
From page :
6252
To page :
6263
Abstract :
Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine pharmacophore shared by all aminoglycoside antibiotics that contain the 2-deoxystreptamine ring. A discovery library of molecules was prepared by attaching different side chains to both sides of the 1,3-diamine motif. Several of these diamines showed inhibitory activity toward two or three different representative aminoglycoside-modifying enzymes (AGMEs). These studies yielded the first non-carbohydrate inhibitor N-cyclohexyl-N′-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound G,H) that is competitive with respect to the aminoglycoside binding to the enzyme aminoglycoside-2″-nucleotidyltransferase-Ia (ANT(2″)). Another diamine molecule N-[2-(3,4-dimethoxyphenyl)-ethyl]-N′-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound H,I) was shown to be a competitive inhibitor of two separate enzymes (aminoglycoside-3′-phosphotransferase-IIIa (APH(3′)) and ANT(2″)) with respect to metal–ATP. Thermodynamic and structural-binding properties of the complexes of APH(3′) with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.
Keywords :
aminoglycosides , Inhibitors , drug design , Bacterial resistance
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2005
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1304979
Link To Document :
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