Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Hurdle, Julian G.; O’Neill, Alex J.; Chopra, Ian

doi:10.1128/aac.49.12.4821-4833.2005

Cited by 191 publications

(175 citation statements)

References 92 publications

(180 reference statements)

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“…McC analogues with variable length of the peptide moiety were synthesized and evaluated in order to characterize the substrate preferences of the YejABEF transporter. It was shown that a minimal peptide chain length of 6 amino acids and the presence of an N-terminal formyl-methionyl-arginyl sequence are required for transport.In the current ongoing quest for new antibiotics, aminoacyltRNA synthetases (aaRSs) have been regarded as promising targets (5,11,14). The natural antibiotic microcin C (McC) (Fig.…”

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confidence: 99%

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Characterization of Peptide Chain Length and Constituency Requirements for YejABEF-Mediated Uptake of Microcin C Analogues

et al. 2011

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Microcin C (McC), a natural antibacterial compound consisting of a heptapeptide attached to a modified adenosine, is actively taken up by the YejABEF transporter, after which it is processed by cellular aminopeptidases, releasing the nonhydrolyzable aminoacyl adenylate, an inhibitor of aspartyl-tRNA synthetase. McC analogues with variable length of the peptide moiety were synthesized and evaluated in order to characterize the substrate preferences of the YejABEF transporter. It was shown that a minimal peptide chain length of 6 amino acids and the presence of an N-terminal formyl-methionyl-arginyl sequence are required for transport.In the current ongoing quest for new antibiotics, aminoacyltRNA synthetases (aaRSs) have been regarded as promising targets (5,11,14). The natural antibiotic microcin C (McC) (Fig. 1, compound 1a) targets an aaRS and has been envisaged as a lead compound for further development as an antibacterial agent (17). McC consists of a heptapeptide that is covalently linked through a phosphoramidate bond to adenosine, with, in addition, an aminopropyl moiety esterified to the phosphoramidate linker (4). Once inside a sensitive cell, McC is processed by peptide deformylase and several peptidases that remove the N-terminal formyl group and the peptide part, respectively (7). As a result of intracellular processing, the active compound (compound 2), a modified nonhydrolysable aspartyl-adenylate, is released. Processed McC is a potent inhibitor of aspartyl-tRNA synthetase (AspRS) (8).McC penetrates the outer membrane of the Escherichia coli cell mostly through the OmpF porin, but also through other, yet-unidentified transport systems (M. Novikova, A. Metlitskaya, and K. Severinov, unpublished data), and is subsequently transported through the inner membrane by the YejABEF transporter (10). YejABEF is the only complex responsible for McC transport, since yej mutants are highly resistant to McC and its maturation intermediates and chemical analogues. While intact McC inhibits the growth of sensitive E. coli cells at low micromolar concentrations, processed McC does not affect cell growth, even at millimolar concentrations. Thus, the peptide chain enables McC to function through a Trojan-horse mechanism by promoting active uptake via the YejABEF transporter. The recently improved synthetic approach for the production of McC analogues has led us to investigate the uptake properties of the Yej transporter in more detail. The results obtained could be important for further drug development, where peptides function as carrier moieties for drugs that otherwise would not be able to penetrate the bacterial membranes. Here, we used a number of McC analogues truncated either from their C-or N-terminal sides, or otherwise modified, to determine the minimal peptide chain length sufficient for facilitated transport by Yej. MATERIALS AND METHODSChemistry. Reagents and solvents were purchased from commercial suppliers (Acros, Sigma-Aldrich, Bachem, and Novabiochem) and used as provided unless otherwise indicated....

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confidence: 99%

“…In the current ongoing quest for new antibiotics, aminoacyltRNA synthetases (aaRSs) have been regarded as promising targets (5,11,14). The natural antibiotic microcin C (McC) (Fig.…”

mentioning

confidence: 99%

Characterization of Peptide Chain Length and Constituency Requirements for YejABEF-Mediated Uptake of Microcin C Analogues

et al. 2011

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“…Chemical structure LeuRS residual activity, % Compound Chemical structure LeuRS residual activity, % As a result, it was found two compounds -5-(5-Chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one (compound 2) and 5-(5-Chloro-2-hydroxy-phenylamino)-2H- [1,2,4] triazin-3-one (compound 3) inhibiting M. tuberculosis LeuRS with IC 50 values equal to 7.6 and 7.2 mL, respectively. At the same time, these compounds demonstrate significantly less inhibition efficiency against human cytoplasmic LeuRS (IC 50 ¼ 68.9 and 76.5 mL) ( Table 2).…”

Section: Compoundmentioning

confidence: 99%

“…Aminoacyl-tRNA synthetases (aaRSs) are promising antiinfective drug targets. These enzymes play pivotal role in protein synthesis and have wide evolutionary divergence in prokaryotes and eukaryotes which allow the development of selective aaRSs inhibitors [1][2][3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

Gudzera

Golub

Bdzhola

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…This includes the antibiotic mupirocin, which is used therapeutically as a topical agent targeting the active site of Gram positive isoleucyl-tRNA Ile synthetase (IleRS) [3][4][5] , preventing the formation of isoleucyl-tRNA Ile . However, the lack of systemic efficacy of mupirocin and its inactivity against Gram negative and TB infections 6,7 as well as the rise of mupirocin resistance in MRSA and MSSA 3,8 has increased the need for new inhibitors targeting this class of enzymes.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Tetraphosphoadenosine Drives a Continuous ATP-Release Assay for Aminoacyl-tRNA Synthetases and Other Adenylate-Forming Enzymes

et al. 2013

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Aminoacyl-tRNA synthetases are essential for the correct linkage of an amino acid to its cognate tRNA. The accuracy of this reaction is key to the fidelity of protein synthesis.Tractable, continuous assays are of value both in characterizing the functions of these enzymes and their exploitation as drug targets. Therefore, we have exploited the hitherto unexplored ability of these enzymes to consume the diadenosine nucleotide diadenosine 5',5''' P 1 P 4 tetraphosphate (adenosine tetraphosphoadenosine (Ap 4 A)) with the concomitant production of ATP in a pyrophosphate and amino acid dependent manner to develop such an assay. We have used this assay to probe the stereo-selectivity of amino acid activation by isoleucyl-tRNA Ile and Valyl-tRNA Val synthetases and to identify analogues of intermediates in their catalytic pathway that might facilitate simultaneous targeting of multiple synthetases.Finally we report the utility of Ap 4 A based assays in the screening and subsequent identification of inhibitors of these enzymes, where the kinetics of Ap 4 A utilization allow the detection of inhibitors with nM to mM affinities.

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Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Cited by 191 publications

References 92 publications

Characterization of Peptide Chain Length and Constituency Requirements for YejABEF-Mediated Uptake of Microcin C Analogues

Characterization of Peptide Chain Length and Constituency Requirements for YejABEF-Mediated Uptake of Microcin C Analogues

Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

Adenosine Tetraphosphoadenosine Drives a Continuous ATP-Release Assay for Aminoacyl-tRNA Synthetases and Other Adenylate-Forming Enzymes

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