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Title: Microcin C and Albomycin Analogues with Aryl-tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake
Authors: Vondenhoff, Gaston H
Gadakh, Bharat
Severinov, Konstantin
Van Aerschot, Arthur # ×
Issue Date: Sep-2012
Publisher: Wiley-VCH
Series Title: Chembiochem vol:13 issue:13 pages:1959-1969
Article number: 10.1002/cbic.201200174
Abstract: In 1998, Cubist Pharmaceuticals patented a series of aminoacyl tRNA synthetase (aaRS) inhibitors based on aminoacyl sulfamoyladenosines (aaSAs), in which the adenine was substituted by aryl-tetrazole moieties linked to the ribose fragment by a two-carbon spacer. Although potent and specific inhibitors of bacterial IleRS, these compounds did not prove successful in vivo due to low cell permeability and strong binding to serum albumin. In this work, we attempted to improve these compounds by combining them with microcin C (McC) or albomycin (i.e., siderophore-drug conjugate (SDC)) transport modules. We found that aryl-tetrazole variants of McC and albomycin still lacked antibacterial activity. However, these compounds were readily processed by E. coli aminopeptidases with the release of toxic aaRS inhibitors. Hence, the lack of activity in whole-cell assays was due to an inability of the new compounds to be taken up by the cells, thus indicating that the nucleotide moieties of McC and albomycin strongly contribute to facilitated transport of these compounds inside the cell.
URI: 
ISSN: 1439-4227
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry
× corresponding author
# (joint) last author

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