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.
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.
authors: Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven, Belgium.
authors: Gaston H
authors: GH
authors: Vondenhoff
authors: Bharat
authors: B
authors: Gadakh
authors: Konstantin
authors: K
authors: Severinov
authors: Arthur
authors: A
authors: Van Aerschot
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001430:Bacteriocins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D005291:Ferrichrome / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D013777:Tetrazoles; C020411:microcin; D005291:Ferrichrome; C045574:1H-tetrazole; C015657:albomycin; D000604:Amino Acyl-tRNA Synthetases