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.

Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development

“…To further explore this, we carried out C-terminal functionalization using the ethylenediamine-functionalized near-IR dye silicon-rhodamine 30 (H 2 NenSiR) on fully acetylated precursor 1a to avoid decomposition of the hydroxamate. 36 Subsequent deacetylation of 5 followed by debenzylation afforded 7 with quantitative yields. This species was reacted with 1,4-diisothiocyanatobenzene, providing 8 as a light blue solid indicating the presence of SiR within the molecule.…”

Biochemical and Structural Characterization of Mycobacterial Aspartyl-tRNA Synthetase AspS, a Promising TB Drug Target

“…Indeed, several naturally occurring antimicrobials have been shown to be specific aaRSs inhibitors [32] . Among them are Microcin C (McC) produced by Enterobacteriaceae, which inhibits translation by preventing aminoacylation of tRNA Asp by AspS and Tobramycin, an aminoglycoside competitive inhibitor with respect to tRNA Asp [33] – [35] . McC functions through a trojan horse mechanism because it enters the bacterial membrane as a prodrug by facilitated transport, undergoes processing by cellular aminopeptidases and releases a toxic moiety called aspartyl adenylate which inhibits AspS [33] , [36] .…”

Synthesis and Biological Evaluation of Lipophilic Nucleoside Analogues as Inhibitors of Aminoacyl-tRNA Synthetases

“…The primary reason for the failure of antibacterial lead molecules discovered after a rational design approach by SAR, is their limited permeability through the bacterial membrane. In the past, trying to overcome the permeability issue of aaSA and their derivatives, our group already synthesized several conjugates comprising of aaSA analogues coupled with various transporter peptide [17][18][19][20][21] or siderophores [21]. However, we achieved limited success due to tedious synthesis, purification, and stability of peptide and siderophore coupled compounds.…”

“…In the past, our group has tried such a Trojan-horse approach to promote the uptake of aaSA analogues and provide antibacterial activity without success [17][18][19][20][21]. An alternative strategy to increase the permeability of compounds is based on increasing the lipophilicity, especially for polar compounds.…”