Thiostrepton and Related Antibiotics

Cundliffe, Eric

doi:10.1007/978-3-642-46403-4_18

Cited by 8 publications

(4 citation statements)

References 48 publications

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“…The mode of action of thiostrepton is reviewed elsewhere (Cundliffe, 1979) but, in summary, the drug inhibits various processes associated with the 'GTP hydrolysis centre' of the ribosome, including the binding of guanine nucleotides, of elongation factor proteins and of tRNA. Recently, we demonstrated that a tight binding site for thiostrepton can be constructed in vitro using only 23s rRNA and ribosomal protein L11 .…”

Section: Introductionmentioning

confidence: 99%

Purification and Properties of an RNA Methylase Produced by Streptomyces azureus and Involved in Resistance to Thiostrepton

Thompson

Cundliffe

1981

Microbiology

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Ribosomes of Streptomyces azureus, the thiostrepton producer, are resistant to the drug due to the action of an RNA-pentose methylase which acts on 23s ribosomal RNA. This enzyme, which is active in vitro on ribosomal RNA from other bacteria (e.g. Escherichia coli), employs S-adenosylmethionine as cofactor to catalyse the formation of a single residue of 2'-O-methyladenosine. The 'thiostrepton-resistance methylase' has been purified 1 1 000-fold (although not to homogeneity) and eluted from gel filtration columns with an apparent molecular weight of 35000 to 38000. The preferred substrate for the methylase was phenol-extracted 23s RNA. In contrast, mature 50s ribosomal subunits were unaffected by the enzyme although protein-deficient core particles, prepared by exposure of ribosomes to LiCl, retained partial substrate activity. Significantly, the methylase was inactive on the complex of 23s RNA with ribosomal protein L1 1.

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Section: Introductionmentioning

confidence: 99%

Purification and Properties of an RNA Methylase Produced by Streptomyces azureus and Involved in Resistance to Thiostrepton

Thompson

Cundliffe

1981

Microbiology

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“…This latter measured the ability of reconstituted particles to form complexes with elongation factor EF-G and GTP (or GDP) in the presence of fusidic acid (1). Formation of such complexes is inhibited specifically by antibiotics of the thiostrepton group (3). As shown in Table 3, all hybrid particles reconstituted showed good activity in complex formation, particularly so when one considers that purified factor EF-G was available only from Escherichia coli.…”

Section: Resultsmentioning

confidence: 96%

Resistance to thiostrepton, siomycin, and sporangiomycin in actinomycetes that produce them

Thompson¹,

Cundliffe²

1980

J Bacteriol

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The antibiotics thiostrepton, siomycin, and sporangiomycin are closely related both in structure and in mode of action. Actinomycetes which produce this group of compounds possess ribonucleic acid-pentose methylases, which act upon 23S ribosomal ribonucleic acid and render ribosomes resistant to the action of these antibiotics. This is achieved via the formation of a single residue of 2'-O-methyladenosine per ribosome.

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“…The latter three compounds inhibit ribosomal functions other than the binding of tRNA to the A-site (Nierhaus & Wittmann, 1980;Oleinick, 1975;Nathans, 1967;Wallace et al, 1979). In contrast, compounds that reduced the accumulation of (p)ppGpp and the decrease of GTP may interfere (directly or indirectly) with the attachment of aminoacyl-tRNA (and therefore presumably also uncharged tRNA) to the A-site; such an interference has been observed for fusidate (Tanaka, 1973), tetracycline (Kaji & Ryoji, 1979) and a small effect for thiostrepton (Cundliffe, 1979) and streptomycin (Wallace et al, 1979), and it has been suggested for chloramphenicol (Pongs, 1979) and lincomycin (Chang, 1979) from studies on the binding of small terminal fragments of tRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Lincomycin has a specific effect also in E. coli and Vibrio cholerae where it stimulates an increase in the rate of toxin production (Levner et al, 1980). The single-site binding can also explain the effect of thiostrepton which binds to the 50S ribosomal subunit and inhibits (in E. coli) mainly the GTP hydrolysis associated with IF-2, EF-Tu and EF-G and the binding of aminoacyl-tRNA to the A-site (Cundliffe, 1979). Thiostrepton does not interfere only with the stringent response, because it also prevented sporulation even at a concentration of only 4 μg ml"', at which it did not prevent the accumulation of (p)ppGpp.…”

Section: Discussionmentioning

confidence: 99%

Effect of Antibiotics on Sporulation Caused by the Stringent Response in Bacillus subtilis

Ochi

Freese

1983

Microbiology

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We have examined in Bacillus subtilis how antibiotics that inhibit protein or RNA synthesis affect the stringent response (i.e. accumulation of (p)ppGpp) and the resulting decrease of GTP and sporulation. All antibiotics used inhibited sporulation completely at concentrations at which they inhibited growth only partially and in most cases only slightly. At these concentrations, some antibiotics (chloramphenicol, fusidic acid, lincomycin, tetracycline) abolished the stringent control, others lowered it. Sporulation inhibited by chloramphenicol or fusidic acid could be almost completely restored by addition of 0-2-0-5 mM-decoyinine, an inhibitor of GMP synthetase. The inhibition of sporulation by tetracycline and streptomycin, or by the RNA polymerase inhibitors rifampin and lipiarmycin, was partially counteracted by decoyinine, whereas the inhibition by lincomycin or by compounds that did not interfere with the stringent response could not be overcome by decoyinine addition. In mutants resistant to erythromycin, or lincomycin or thiostrepton, sporulation was no longer inhibited by that particular antibiotic but was still sensitive to the other two.The results show that some antibiotics inhibited sporulation because they prevented the decrease of GTP needed to initiate sporulation caused by the stringent response. Other antibiotics inhibited sporulation by interfering with specific (ribosomal) functions either needed to maintain a certain metabolic state or specifically required for the synthesis of.sporulationspecific proteins. t Present address:

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Thiostrepton and Related Antibiotics

Cited by 8 publications

References 48 publications

Purification and Properties of an RNA Methylase Produced by Streptomyces azureus and Involved in Resistance to Thiostrepton

Purification and Properties of an RNA Methylase Produced by Streptomyces azureus and Involved in Resistance to Thiostrepton

Resistance to thiostrepton, siomycin, and sporangiomycin in actinomycetes that produce them

Effect of Antibiotics on Sporulation Caused by the Stringent Response in Bacillus subtilis

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