Microcin C and Albomycin Analogues with Aryl-tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake

Gaston H. Vondenhoff, Bharat Gadakh, Konstantin Severinov, Arthur Van Aerschot

Research output: Contribution to journalArticle

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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. Synthetases' Achilles' heel? Selective inhibition of bacterial aminoacyl tRNA synthetases was previously accomplished by using aminoacyl sulfamoyladenosines and substituting aryltetrazole moieties for the adenine heterocycle. While these compounds did not prove successful in vivo, conjugation to peptidic Trojan horses or siderophore drug conjugate (SDC) transport modules envisaged improved uptake.

Original languageEnglish (US)
Pages (from-to)1959-1969
Number of pages11
JournalChemBioChem
Volume13
Issue number13
DOIs
StatePublished - Sep 3 2012

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Keywords

  • AaRS
  • Aminoacyl tRNA synthetases
  • Antibiotics
  • Inhibitors
  • Microcin C
  • Siderophores

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