Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes

Welch K., Virga K., Whittemore N., Ozen C., Wright E., Brown C., ...Daha Fazla

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.13, sa.22, ss.6252-6263, 2005 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 13 Sayı: 22
  • Basım Tarihi: 2005
  • Doi Numarası: 10.1016/j.bmc.2005.06.059
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.6252-6263
  • Anahtar Kelimeler: aminoglycosides, drug design, inhibitors, bacterial resistance, OVEREXPRESSION, BINDING, PURIFICATION, ANTIBIOTICS, INACTIVATION, STREPTOMYCIN, ENTEROCOCCUS, CLONING, DESIGN, SITE
  • Orta Doğu Teknik Üniversitesi Adresli: Hayır

Özet

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-la (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. (c) 2005 Elsevier Ltd. All rights reserved.