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tRNAs as antibiotic targets.

Chopra S, Reader J - Int J Mol Sci (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: . schopra@email.unc.edu.

ABSTRACT
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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Chemical structures of tRNA based inhibitors of aminoacyl-tRNA synthetases (AN2690 and agrocin 84/TM84) and ribosome (thermorubin and blasticidin S).
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ijms-16-00321-f003: Chemical structures of tRNA based inhibitors of aminoacyl-tRNA synthetases (AN2690 and agrocin 84/TM84) and ribosome (thermorubin and blasticidin S).

Mentions: A number of aaRSs, which catalyze the aminoacylation of branched chain amino acids, such as LeuRS, valyl-tRNA synthetase (ValRS) and IleRS, possess an additional proofreading domain called the CP1 domain [77,78,79]. This domain is located about ~30 Å away from the aminoacylation active site and is involved in recognizing and hydrolyzing misacylated amino acids on the 3'-end of the tRNALeu. Recently, a pharmaceutical company (Anacor) used combinatorial screening of a library of organoboron compounds and discovered a novel synthetic compound, AN2690 (Figure 3) that inhibited a fungal LeuRS from the yeast Saccharomyces cerevisiae. AN2690 (5-fluoro-1,3 dihydro-1-hydroxy-2, 1-benzoxazole) was found to show broad-spectrum activity with minimum inhibitory concentration (MIC) in the range of 0.5 to 1 μg/mL. Importantly, when S. cerevisiae colonies resistant to AN2690 were generated, the mutations were all tracked to the CDC60 gene, which encodes the cytoplasmic LeuRS [80]. Most interestingly the mutations were found to all be located in the LeuRS editing domain [81]. This observation led to the discovery that AN2690 works by binding to the enzyme’s editing domain [80] in a non-competitive manner. Specifically, contacts made with the 2' and 3'-oxygen atoms of the ribose of the 3'-terminal adenosine of tRNA leads to the formation of a stable tRNALeu-AN2690 adduct [80]. This adduct is effectively trapped in the editing domain preventing further rounds of aminoacylation occurring on the enzyme.


tRNAs as antibiotic targets.

Chopra S, Reader J - Int J Mol Sci (2014)

Chemical structures of tRNA based inhibitors of aminoacyl-tRNA synthetases (AN2690 and agrocin 84/TM84) and ribosome (thermorubin and blasticidin S).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307249&req=5

ijms-16-00321-f003: Chemical structures of tRNA based inhibitors of aminoacyl-tRNA synthetases (AN2690 and agrocin 84/TM84) and ribosome (thermorubin and blasticidin S).
Mentions: A number of aaRSs, which catalyze the aminoacylation of branched chain amino acids, such as LeuRS, valyl-tRNA synthetase (ValRS) and IleRS, possess an additional proofreading domain called the CP1 domain [77,78,79]. This domain is located about ~30 Å away from the aminoacylation active site and is involved in recognizing and hydrolyzing misacylated amino acids on the 3'-end of the tRNALeu. Recently, a pharmaceutical company (Anacor) used combinatorial screening of a library of organoboron compounds and discovered a novel synthetic compound, AN2690 (Figure 3) that inhibited a fungal LeuRS from the yeast Saccharomyces cerevisiae. AN2690 (5-fluoro-1,3 dihydro-1-hydroxy-2, 1-benzoxazole) was found to show broad-spectrum activity with minimum inhibitory concentration (MIC) in the range of 0.5 to 1 μg/mL. Importantly, when S. cerevisiae colonies resistant to AN2690 were generated, the mutations were all tracked to the CDC60 gene, which encodes the cytoplasmic LeuRS [80]. Most interestingly the mutations were found to all be located in the LeuRS editing domain [81]. This observation led to the discovery that AN2690 works by binding to the enzyme’s editing domain [80] in a non-competitive manner. Specifically, contacts made with the 2' and 3'-oxygen atoms of the ribose of the 3'-terminal adenosine of tRNA leads to the formation of a stable tRNALeu-AN2690 adduct [80]. This adduct is effectively trapped in the editing domain preventing further rounds of aminoacylation occurring on the enzyme.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: . schopra@email.unc.edu.

ABSTRACT
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.

Show MeSH