Aminoacyl-tRNA synthetases: essential and still promising targets for new anti-infective agents

Ochsner, Urs A.; Sun, Xicheng; Jarvis, Thale C.; Critchley, Ian A.; Janjić, Nebojša

doi:10.1517/13543784.16.5.573

Cited by 89 publications

(88 citation statements)

References 125 publications

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“…This precedent indicated to us the potential for developing selective inhibitors of aaRS enzymes for other infectious pathogens such as trypanosomes. The MetRS enzyme was a particularly attractive target for piggyback drug development for neglected tropical diseases (9) because of the existence of potent MetRS inhibitors under development in Pharma for other indications (22). The similarities between the bacterial MetRS enzymes and those of T. brucei and T. cruzi led to our hypothesis that the existing compounds might bind trypanosomal MetRS enzymes and give rise to antitrypanosomal activity.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice

Shibata

Gillespie

Kelley

et al. 2011

Antimicrob Agents Chemother

125

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Human African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS of Trypanosoma brucei demonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on the T. brucei MetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms of T. brucei cultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition and T. brucei growth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 M, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of the T. brucei MetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice

Shibata

Gillespie

Kelley

et al. 2011

Antimicrob Agents Chemother

125

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“…Their ubiquitous nature, high degree of conservation within a broad spectrum of bacterial species, and considerable divergence between prokaryotic and eukaryotic enzymes have made AaRSs the subject of multiple antibacterial programs (12,13), although no other AaRS inhibitor has reached the market to date.…”

mentioning

confidence: 99%

Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

O’Dwyer

Spivak

Ingraham

et al. 2015

Antimicrob Agents Chemother

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e GSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with >32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coli isolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coli isolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.) A pproximately 5% of patients admitted to hospitals in the United States develop nosocomial infections that increase not only patient mortality (1) but also hospitalization time and cost of treatment (2, 3). In the United States, Gram-negative bacterial pathogens, such as Escherichia coli, Klebsiella pneumoniae/Klebsiella oxytoca, Pseudomonas aeruginosa, and Acinetobacter baumannii, are responsible for 35% of the most common hospitalacquired infections (HAIs) or conditions, including urinary tract infections (UTIs), pneumonia, and surgical site and bloodstream infections. Furthermore, Ͼ70% of the bacteria causing HAIs are resistant to at least one of the most commonly used antibiotics (4-6). The continuing emergence of resistance has compromised treatment options for Gram-negative bacterial pathogens and forced the use of polymyxins (7), an old antibiotic class with nephrotoxicity issues. Despite the clear need for alternatives to treat these multidrug-resistant life-threatening pathogens, a review of the antibacterial pipeline reveals a scarcity of new antibiotic candidates (8).Aminoacyl-tRNA synthetases (AaRSs) play an essential role in protein synthesis (9) and have been clinically validated to be antibacterial targets of mupirocin (10), an inhibitor of isoleucyltRNA synthetase that has been successfully used since 1985 in the topical treatment of Gram-positive bacterial skin infections (11). Their ubiquitous nature, high degree of conservation within a broad spectrum of bacterial species, and considerable divergence...

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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.…”

mentioning

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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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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Aminoacyl-tRNA synthetases: essential and still promising targets for new anti-infective agents

Cited by 89 publications

References 125 publications

Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice

Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice

Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

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

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