Indolmycin Inhibits Prokaryotic Tryptophanyl-tRNA Ligase

Werner, Rolf G.; Thorpe, Lance F.; Reuter, W; Nierhaus, Knud H.

doi:10.1111/j.1432-1033.1976.tb10758.x

Cited by 79 publications

(54 citation statements)

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“…To determine whether (p)ppGpp generation was specific to inhibition of isoleucyl tRNA synthetase by mupirocin, S. aureus 8325-4 and S. aureus Carter 7 (a clinical strain highly resistant to mupirocin [12]) were treated with indolmycin (an inhibitor of tryptophanyl tRNA synthetase but not isoleucyl tRNA synthetase [32]) at 10ϫ MIC. Accumulation of (p)ppGpp was indeed detected in both of these strains.…”

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confidence: 99%

Occurrence of the regulatory nucleotides ppGpp and pppGpp following induction of the stringent response in staphylococci

1995

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The stringent response in Escherichia coli and many other organisms is regulated by the nucleotides ppGpp and pppGpp. We show here for the first time that at least six staphylococcal species also synthesize ppGpp and pppGpp upon induction of the stringent response by mupirocin. Spots corresponding to ppGpp and pppGpp on thin-layer chromatograms suggest that pppGpp is the principal regulatory nucleotide synthesized by staphylococci in response to mupirocin, rather than ppGpp as in E. coli.Bacteria adapt to amino acid or carbon source insufficiency by a complex series of regulatory events known as the stringent response (reviewed in reference 4). In Escherichia coli, for example, amino acid starvation leads to an accumulation of uncharged cognate tRNA. When the ratio of charged to uncharged tRNA falls below a critical threshold (24), occupation of the vacant mRNA codon at the ribosomal A site by uncharged cognate tRNA leads to stalling of peptide chain elongation and synthesis of the nucleotides pppGpp and ppGpp from GTP and ATP in an idling reaction involving RelA (2, 9, 13). Intracellular concentrations of (p)ppGpp are controlled by the relA gene, encoding the ribosome-dependent (p)ppGpp synthetase I, or stringent factor (19), and the spoT gene, encoding the ribosome-independent ppGpp 3Ј-pyrophosphohydrolase/ppGpp synthetase II (14,33).Induction of the stringent response rapidly reduces the synthesis of mRNA because of inhibition of RNA polymerase by ppGpp (28,31). This coincides with the down-regulation of a wide range of energetically demanding cellular processes, including the synthesis of stable RNA, DNA, protein, and peptidoglycan. Close coordination between transcription and translation can be maintained through the effects of the stringent response on the regulation of individual ribosomal proteins; elongation factors G, Tu, and Ts; certain aminoacyl tRNA synthetases; and stationary-phase-specific sigma factor ( s ) (11). Ultimately, changes such as these enhance survival in a nutrient-poor environment.The antibiotic mupirocin (30) produces cellular effects similar to those of isoleucine starvation by preventing the charging of tRNA Ile due to inhibition of isoleucyl tRNA synthetase in E. coli (16,17), Staphylococcus aureus (5), and other organisms, thereby inhibiting protein synthesis. In the presence of mupirocin, RNA synthesis in E. coli and S. aureus is also inhibited as a consequence of the stringent response; however, this inhibition can be reversed by chloramphenicol (15), which in E. coli, binds close to the binding site for the terminal CCA of aminoacyl tRNA in the peptidyl transferase A site (23) and reduces the amount of RelA-dependent (p)ppGpp synthesis (8, 10). A stringent response mediated by (p)ppGpp has been detected in some gram-positive and gram-negative bacteria and higher organisms after amino acid starvation or induction by a variety of antibiotics (7,18,26). However, in halobacteria (25) and streptococci (21), stringency is not necessarily coupled with (p)ppGpp production. Thus, in S...

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Occurrence of the regulatory nucleotides ppGpp and pppGpp following induction of the stringent response in staphylococci

1995

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“…4, structure 5), was first isolated from Streptomyces griseus (ATCC 12648) and patented by Pfizer in 1965 (8,34). Indolmycin is a potent and selective inhibitor of bacterial tryptophanyl-tRNA synthetase (50% inhibitory concentration [IC 50 ] ϭ 9.25 nM for E. coli TrpRS) and displays minimal activity against the eukaryotic counterpart (IC 50 ϭ 4.04 mM for bovine liver TrpRS) (52,89). However, it is relatively inactive against several common bacterial pathogens, including streptococci, enterococci, and members of the family Enterobacteriaceae (52).…”

Section: Other Natural Products Which Inhibit Trna Synthetasesmentioning

confidence: 99%

Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Hurdle

O’Neill

Chopra

2005

Antimicrob Agents Chemother

188

172

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“…Indolmycin ( Fig. 1), produced by Streptomyces griseus ATCC 12648 (22,23), is a structural analog of L-tryptophan that competitively inhibits bacterial tryptophanyl-tRNA synthetases (26). In vitro enzymatic assays showed that TrpRS2 is indolmycin sensitive, whereas TrpRS1 is highly resistant to the antibiotic (19).…”

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confidence: 99%