title: Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes.
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 (ANT2''). 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 (APH3') and ANT2'') with respect to metal-ATP. Thermodynamic and structural-binding properties of the complexes of APH3' with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.
authors.affiliation: Department of Biochemistry, Cellular and Molecular Biology and Center of Excellence for Structural Biology, University of Tennessee, Walters Life Sciences Building M407, Knoxville, TN 37996-0840, USA.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Welch
authors.forename: Kristopher G
authors.initials: KG
authors.lastname: Virga
authors.forename: Neil A
authors.initials: NA
authors.lastname: Whittemore
authors.forename: Can
authors.initials: C
authors.lastname: Ozen
authors.forename: Edward
authors.initials: E
authors.lastname: Wright
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Brown
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Engin H
authors.initials: EH
authors.lastname: Serpersu
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D002151:Calorimetry; D003959:Diamines / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006595:Hexosamines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D003959:Diamines; D004791:Enzyme Inhibitors; D006595:Hexosamines; C002980:streptamine; D010770:Phosphotransferases