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Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes
Date
2005-11-15
Author
Welch, KT
Virga, KG
Whittemore, NA
Özen, Can
Wright, E
Brown, CL
Lee, RE
Serpersu, EH
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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
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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.
Subject Keywords
Aminoglycosides
,
Drug design
,
Inhibitors
,
Bacterial resistance
URI
https://hdl.handle.net/11511/29997
Journal
BIOORGANIC & MEDICINAL CHEMISTRY
DOI
https://doi.org/10.1016/j.bmc.2005.06.059
Collections
Graduate School of Natural and Applied Sciences, Article
Citation Formats
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BibTeX
K. Welch et al., “Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes,”
BIOORGANIC & MEDICINAL CHEMISTRY
, vol. 13, no. 22, pp. 6252–6263, 2005, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/29997.