Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors

Cressina, Elena; Lloyd, Adrian J.; Pascale, Gianfranco De; Mok, Bwy; Caddick, Stephen; Roper, David I.; Dowson, Christopher G.; Bugg, Timothy D. H.

doi:10.1016/j.bmc.2009.03.028

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…In addition, two families of tRNA-dependent transferases, MurMN and FemABX exist to use l -Ala-tRNA Ala as substrates for l -Ala transfer to a peptidoglycan cross-bridge. MurM is involved in the addition of the first amino acids (Ala or Ser) to the cross-bridge, MurN—of the second amino acid (Ala) (62) to lipid intermediate II in peptidoglycan biosynthesis (63). Recently, it was shown that the trans- editing activity of MurM does not require the presence of its second lipid substrate (61) and this protein is able to deacylate not only l -Ala/ l -Ser-tRNA Ala but also l -Ala-tRNA Ser /tRNA Phe /tRNA Lys and Ser-tRNA Phe (64).…”

Section: Discussionmentioning

confidence: 99%

Stereospecificity control in aminoacyl-tRNA-synthetases: new evidence of d-amino acids activation and editing

Rybak

Rayevsky

Gudzera

et al. 2019

Nucleic Acids Research

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The homochirality of amino acids is vital for the functioning of the translation apparatus. l-Amino acids predominate in proteins and d-amino acids usually represent diverse regulatory functional physiological roles in both pro- and eukaryotes. Aminoacyl-tRNA-synthetases (aaRSs) ensure activation of proteinogenic or nonproteinogenic amino acids and attach them to cognate or noncognate tRNAs. Although many editing mechanisms by aaRSs have been described, data about the protective role of aaRSs in d-amino acids incorporation remained unknown. Tyrosyl- and alanyl-tRNA-synthetases were represented as distinct members of this enzyme family. To study the potential to bind and edit noncognate substrates, Thermus thermophilus alanyl-tRNA-synthetase (AlaRS) and tyrosyl-tRNA-synthetase were investigated in the context of d-amino acids recognition. Here, we showed that d-alanine was effectively activated by AlaRS and d-Ala-tRNAAla, formed during the erroneous aminoacylation, was edited by AlaRS. On the other hand, it turned out that d-aminoacyl-tRNA-deacylase (DTD), which usually hydrolyzes d-aminoacyl-tRNAs, was inactive against d-Ala-tRNAAla. To support the finding about DTD, computational docking and molecular dynamics simulations were run. Overall, our work illustrates the novel function of the AlaRS editing domain in stereospecificity control during translation together with trans-editing factor DTD. Thus, we propose different evolutionary strategies for the maintenance of chiral selectivity during translation.

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Section: Discussionmentioning

confidence: 99%

Stereospecificity control in aminoacyl-tRNA-synthetases: new evidence of d-amino acids activation and editing

Rybak

Rayevsky

Gudzera

et al. 2019

Nucleic Acids Research

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“…From the design of inhibitors targeting ASL region of tRNA [ 213 ] and essential tRNA modification enzymes, to the discovery of new tRNA-dependent inhibition mechanisms against aaRSs, such as those employed by AN2690 [ 80 ] and agrocin 84 [ 109 ], the future for developing tRNA targeting antibiotics looks promising. Finally, tRNAs have been found to play an increasing number of non-canonical roles in microbes and these maybe another rich vein to mine novel drugs and targets [ 169 , 170 ].…”

Section: Discussionmentioning

confidence: 99%

“…Using this approach, an analogue of aminoacyl-tRNA linked to 1, 2, 4 oxazolidine ring has been synthesized that inhibits Fem transferases in Weissella viridescens (FemX Wv (IC 50 = 1.4 μM) [ 169 ]. Similarly, MurM from S. pneumoniae was inhibited by a 2'-deoxyadenosine 3'-phosphonate analogue [ 170 ].…”

Section: Antibiotics Affecting Non-canonical Roles Of Trnamentioning

confidence: 99%

tRNAs as Antibiotic Targets

Chopra¹,

Reader²

2014

IJMS

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Transfer RNAs (tRNAs) are central players in the protein translation machinery and as such are prominent targets for a large number of natural and synthetic antibiotics. This review focuses on the role of tRNAs in bacterial antibiosis. We will discuss examples of antibiotics that target multiple stages in tRNA biology from tRNA biogenesis and modification, mature tRNAs, aminoacylation of tRNA as well as prevention of proper tRNA function by small molecules binding to the ribosome. Finally, the role of deacylated tRNAs in the bacterial “stringent response” mechanism that can lead to bacteria displaying antibiotic persistence phenotypes will be discussed.

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“…Figure 4 highlights differences in tRNAs used in peptidoglycan synthesis versus isoacceptors used in translation. Inhibitors are being developed by the synthesis of stable tRNA analogs, 2′‐deoxy‐adenosine, adenosine 3′‐phosphate analogs, and aryl sulfanilamides, all of which mimic the tetrahedral transition state thought to be part of the MurM catalyzed reaction 133–136…”

Section: Building Bridges: Role Of Aa‐trna In Peptidoglycan Linkagesmentioning

confidence: 99%

Roles of tRNA in cell wall biosynthesis

Dare

Ibba

2012

WIREs RNA

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Recent research into various aspects of bacterial metabolism such as cell wall and antibiotic synthesis, degradation pathways, cellular stress, and amino acid biosynthesis has elucidated roles of aminoacyl-transfer ribonucleic acid (aa-tRNA) outside of translation. Although the two enzyme families responsible for cell wall modifications, aminoacyl-phosphatidylglycerol synthases (aaPGSs) and Fem, were discovered some time ago, they have recently become of intense interest for their roles in the antimicrobial resistance of pathogenic microorganisms. The addition of positively charged amino acids to phosphatidylglycerol (PG) by aaPGSs neutralizes the lipid bilayer making the bacteria less susceptible to positively charged antimicrobial agents. Fem transferases utilize aa-tRNA to form peptide bridges that link strands of peptidoglycan. These bridges vary among the bacterial species in which they are present and play a role in resistance to antibiotics that target the cell wall. Additionally, the formation of truncated peptides results in shorter peptide bridges and loss of branched linkages which makes bacteria more susceptible to antimicrobials. A greater understanding of the structure and substrate specificity of this diverse enzymatic family is necessary to aid current efforts in designing potential bactericidal agents. These two enzyme families are linked only by the substrate with which they modify the cell wall, aa-tRNA; their structure, cell wall modification processes and the physiological changes they impart on the bacterium differ greatly.

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Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors

Cited by 15 publications

References 26 publications

Stereospecificity control in aminoacyl-tRNA-synthetases: new evidence of d-amino acids activation and editing

Stereospecificity control in aminoacyl-tRNA-synthetases: new evidence of d-amino acids activation and editing

tRNAs as Antibiotic Targets

Roles of tRNA in cell wall biosynthesis

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