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 language | English (US) |
|---|---|
| Pages (from-to) | 1959-1969 |
| Number of pages | 11 |
| Journal | ChemBioChem |
| Volume | 13 |
| Issue number | 13 |
| DOIs | |
| State | Published - 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
Cite this
}
Microcin C and Albomycin Analogues with Aryl-tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake. / Vondenhoff, Gaston H.; Gadakh, Bharat; Severinov, Konstantin; Van Aerschot, Arthur.
In: ChemBioChem, Vol. 13, No. 13, 03.09.2012, p. 1959-1969.Research output: Contribution to journal › Article
TY - JOUR
T1 - Microcin C and Albomycin Analogues with Aryl-tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake
AU - Vondenhoff, Gaston H.
AU - Gadakh, Bharat
AU - Severinov, Konstantin
AU - Van Aerschot, Arthur
PY - 2012/9/3
Y1 - 2012/9/3
N2 - 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.
AB - 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.
KW - AaRS
KW - Aminoacyl tRNA synthetases
KW - Antibiotics
KW - Inhibitors
KW - Microcin C
KW - Siderophores
UR - http://www.scopus.com/inward/record.url?scp=84865542497&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865542497&partnerID=8YFLogxK
U2 - 10.1002/cbic.201200174
DO - 10.1002/cbic.201200174
M3 - Article
C2 - 22847961
AN - SCOPUS:84865542497
VL - 13
SP - 1959
EP - 1969
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 13
ER -