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PubMed1982

High dimensional structure of the antigen-binding site of anti-viomycin immunoglobulin analyzed by enzyme immunoassay.

Precise immunological recognition of anti-viomycin antiserum at detailed parts in the structure of viomycin was studied by cross reactivities of the antiserum to viomycin and its ten analogs using an enzyme immunoassay of viomycin. The antiserum clearly recognized all minor modifications in the sixteen membered ring of viomycin, indicating that the antiserum clearly recognizes the whole structure of the sixteen membered ring. Recognition of the antiserum on the beta-lysine terminus was also examined showing that the antiserum was also recognized on this part. Thus, the anti-viomycin antiserum was deduced to recognize the whole structure of viomycin, from which the deduction was made that the anti-viomycin antibodies in the antiserum must possess cavities fitting the whole structure of viomycin. The crystal dimensions of viomycin are 13 A in length, 8 A in width, and 7 A in depth. Thus, the high dimensional structure of the binding sites of the anti-viomycin antibodies was deduced to possess cavities of a similar size to that of viomycin.

Animals↗

PubMed1999

The antibiotic viomycin as a model peptide for the origin of the co-evolution of RNA and proteins.

Viomycin is an RNA-binding peptide antibiotic which inhibits prokaryotic protein synthesis and group I intron self-splicing. This antibiotic enhances the activity of the ribozyme derived from the Neurospora crassa VS RNA, and at sub-inhibitory concentrations it induces the formation of group I intron oligomers. Here, we address the question whether viomycin exerts specificity in the promotion of RNA-RNA interactions. In an in vitro selection experiment we tested the ability of viomycin to specifically select molecules out of an RNA pool. Group I intron RNA was incubated with a pool of random sequence RNA, or with a pool of RNA molecules which had previously been enriched for viomycin-binding RNAs. Viomycin was added in order to select viomycin-binding RNAs and to guide their interaction with the intron RNA resulting in recombinant molecules. Viomycin was indeed capable of specifically selecting RNA molecules which contain viomycin-binding sites promoting recombination. These results suggest that small peptides are able to play the role of selector molecules in a putative 'RNA World' launching the co-evolution of RNA and proteins into an 'RNA-protein World'.

Anti-Bacterial Agents↗

PubMed2003

Identification and cloning of genes encoding viomycin biosynthesis from Streptomyces vinaceus and evidence for involvement of a rare oxygenase.

The tuberactinomycins are a family of basic cyclic peptides that exhibit potent antitubercular activity. These peptides are characterized by the presence of an amino acid with a 6-membered cyclic guanidine side chain (capreomycidine) and two or more 2,3-diaminopropionate residues. Viomycin (tuberactinomycin B) is a well-studied member of the family, was once prescribed for the treatment of tuberculosis, and has been shown to block translocation during protein biosynthesis. The gene cluster encoding viomycin biosynthesis was identified and cloned from Streptomyces vinaceus. The cluster was identified by screening genomic libraries with the viomycin phosphotransferase self-resistance gene (vph) and non-ribosomal peptide synthetase (NRPS) gene probes amplified from S. vinaceus genomic DNA. The viomycin cluster was localized to ca. 120 kb of contiguous DNA defined by four overlapping cosmid inserts. Each cosmid hybridized with one or more peptide synthetase gene probes and two also hybridized with vph. Confirmation that the cluster encoded viomycin biosynthesis was obtained from the disruption of two NRPS adenylation domains. Partial sequence analysis revealed an ORF (svox) predicted to encode a rare non-heme iron, alpha-ketoglutarate dependent oxygenase proposed to function in the oxidative cyclization of arginine to the capreomycidine residue. Insertional disruption of svox resulted in complete loss of viomycin production, confirming its involvement in the pathway.

Amino Acid Sequence↗

PubMed1997

In vitro selection of a viomycin-binding RNA pseudoknot.

BACKGROUND: The peptide antibiotic viomycin inhibits ribosomal protein synthesis, group I intron self-splicing and self-cleavage of the human hepatitis delta virus ribozyme. To understand the molecular basis of RNA binding and recognition by viomycin, we isolated a variety of novel viomycin-binding RNA molecules using in vitro selection. RESULTS: More than 90% of the selected RNA molecules shared one continuous highly conserved region of 14 nucleotides. Mutational analyses, structural probing, together with footprinting experiments by chemical modification, and Pb2+-induced cleavage showed that this conserved sequence harbours the antibiotic-binding site and forms a stem-loop structure. Moreover, the loop is engaged in a long-range interaction forming a pseudoknot. CONCLUSIONS: A comparison between the novel viomycin-binding motif and the natural RNA target sites for viomycin showed that all these segments form a pseudoknot at the antibiotic-binding site. We therefore conclude that this peptide antibiotic has a strong selectivity for particular RNA pseudoknots.

Anti-Bacterial Agents↗

PubMed2002

Effect of magnesium ions on the tertiary structure of the hepatitis C virus IRES and its affinity for the cyclic peptide antibiotic viomycin.

A key ion-dependent folding unit within the hepatitis C IRES comprises the IIIef junction and pseudoknot. This region is also important in recruitment of the 40S ribosomal subunit. Here, circular dichroism is used to study the influence of metal ions on the structure and stability of this region. Comparison of the thermal stability of an IRES fragment encompassing subdomains IIIe/f and IV (named 3EF4) with that of a larger fragment also possessing subdomain IIId (3DEF4) indicates an additional stabilizing effect of Mg(2+) ions on the latter fragment. Magnesium and potassium ions stabilize both fragments through nonspecific counterion effects. The additional effect of magnesium on 3DEF4, observed in the absence or presence of 100 mM KCl, is attributed to a nonspecific but high-affinity site for metal ions created by a region of unusual high charge density. Subdomain IIId presumably participates in tertiary packing interactions that provide such a site. Viomycin binds to the full-length IRES and RNA fragments with K(d) values of 25-55 microM. Interestingly, viomycin binding to the two fragments is affected differently by Mg(2+); noncompetitive inhibition of binding to 3DEF4 is observed, whereas binding to 3EF4 is not impaired. Formation of a Mg(2+)-stabilized tertiary fold, involving subdomain IIId, may thereby hinder viomycin binding to 3DEF4 indirectly. Mutational and deletion studies locate viomycin binding within subdomains IIIe/f rather than within the pseudoknot. In pseudoknot mutants, Mg(2+) ions have different effects on viomycin binding and thermal stability, suggesting altered tertiary interactions involving subdomain IIId.

Anti-Bacterial Agents↗

PubMed1978

Viomycin favours the formation of 70S ribosome couples.

The peptide antibiotic viomycin at a concentration of 10 muM inhibits E. coli ribosomes to the extent of about 70% as measured in the poly (U) system, and to about 85% in a natural mRNA (R17) system. Ribosomes from M. smegmatis show no activity at all at this concentration of the antibiotic. Experiments on the Mg+2 dependent dissociation and association of the ribosomal subunits revealed that viomycin stabilizes the 70S couples and promotes association of ribosomal subunits. This response is related to the drug action as indicated by the observation that viomycin resistant strains are not affected by viomycin with respect to dissociation and 70S couple information. A model for the inhibitory action of the drug is proposed.

Depression, Chemical↗

PubMed1977

Cross-resistance in M. tuberculosis to kanamycin, capreomycin and viomycin.

Drug resistant mutants to streptomycin, kanamycin, viomycin, capreomycin, and rifampicin were isolated from four strains of Mycobacterium tuberculosis. The mutants isolated from each parent were then tested for evidence of development of cross-resistance to other drugs. There was no cross-resistance between either streptomycin or rifampicin and any of the other drugs. Complete cross-resistance between viomycin and capreomycin was found. Cross-resistance between kanamycin and capreomycin, and kanamycin and viomycin was variable. A review of the medical histories of 27 patients with kanamycin-resistant tubercle bacilli indicated that cross-resistance with capreomycin and viomycin occurs, but is unpredictable. Because of this variability in cross-resistance and the fact that kanamycin is a more toxic drug than capreomycin, it is suggested that capreomycin be used in the first retreatment regimen for tuberculosis when streptomycin resistance has been demonstrated.

Capreomycin↗

PubMed1995

Viomycin does not stimulate the dissociation of peptidyl-tRNA.

Peptidyl-transfer RNA normally dissociates at a low rate from the ribosomes of Escherichia coli during protein synthesis but accumulates under nonpermissive conditions in cells with a temperature-sensitive allele (pthts) of the gene encoding peptidyl-transfer RNA hydrolase. The antibiotic-hypersensitive strain E. coli DB-11 with the pthts mutation was exposed to viomycin, then placed at nonpermissive temperatures. Under these conditions in the absence of drugs, peptidyl-tRNA accumulates, protein synthesis is inhibited and pthts cells die. When viomycin was present at sufficient concentration to arrest protein synthesis, cell death was not accelerated, error-inducing effects of streptomycin were not counteracted and, at high doses, cytoplasmic accumulation of peptidyl-transfer RNA was slowed down. Blocking the translocation of peptidyl-transfer RNA with viomycin did not stimulate its dissociation from ribosomes. Erythromycin-enhanced cell death was not affected by viomycin at doses sufficient to block amino acid incorporation, suggesting that short peptidyl-transfer RNAs could still be synthesized and dissociated from ribosomes.

Drug Combinations↗

PubMed1980

Dinucleotide codon-anticodon interaction as a minimum requirement for ribosomal aa-tRNA binding: stabilisation by viomycin of aa-tRNA in the A site.

The requirements for the decoding process at the ribosomal A site have been investigated in the presence of viomycin. For these studies natural mRNA was replaced either by the synthetic oligonucleotide A-U-G(-U)n, with 0 less than or equal to n less than or equal to 4, or by a physical mixture of the oligonucleotides A-U-G and various oligo(U) sequences. Thus the effect of the "removal" of selected covalent bonds from the sequence A-U-G(U)n could be studied. When the ribosomal P site contains tRNAMetf, then normally the full hexanucleotide "messenger" A-U-G-U-U-U is needed for the EF-Tu-mediated binding of Phe-tRNA into the A site. However in presence of viomycin the pentanucleotide A-U-G-U-U suffices for this. It is also possible in the presence of viomycin to replace A-U-G-U and U-U. In all the above systems the binding of Phe-tRNA required the presence of EF-Tu and GTP. The results suggest that viomycin reinforces interactions between aa-tRNA and the A site after the codon-anticodon recognition step.

Anticodon↗

PubMed1972

Analysis of ribosomes from viomycin-sensitive and -resistant strains of Mycobacterium smegmatis.

Viomycin-resistant strains were isolated from Mycobacterium smegmatis. Ribosomes were isolated and tested for drug resistance in subcellular systems containing poly(U) as messenger ribonucleic acid. Resistance to viomycin in these strains was due to altered ribosomes. Further analysis showed that viomycin resistance of two mutants with low level resistance (20 mug/ml) was due to altered 30S ribosomal subunits. Another mutant that was highly resistant to viomycin (1 mg/ml), however, had altered 50S ribosomal subunits.

Bacterial Proteins↗

PubMed1980

Viomycin-induced electrolyte abnormalities.

Severe hypokalemia (2.6 mEq/l), hypomagnesemia (0.6 mg/dl), mild hypercalcemia (10.9 mg/dl), and secondary hyperaldosteronism developed in a patient receiving viomycin for pulmonary tuberculosis. Reversible renal wasting of both potassium (K+) and magnesium (Mg++) was documented. Viomycin administered to 40 rats resulted in severe damage to the proximal tubule and mild damage to the distal tubule. THe case report and experimental data suggest viomycin induces proximal tubule dysfunction that results in renal wasting of sodium, K+ and Mg++ and secondary hyperaldosteronism. Hypercalcemia, not previously associated with viomycin therapy, may be secondary to hypomagnesemia-induced hyperparathyroidism.

Adult↗

PubMed1973

The second international reference preparation of viomycin.

The first International Reference Preparation of Viomycin was replaced by the second international reference preparation, consisting of material from the batch that provided the second Working Standard of the US Food and Drug Administration. The International Unit of viomycin was redefined as the activity contained in 0.0012285 mg of the second international reference preparation. Examination of batches of viomycin sulfate from the various sources of production showed that the second international reference preparation was suitable for their assay, whereas a sample previously proposed as the international standard of viomycin was unsatisfactory.

International Cooperation↗

PubMed1979

Interaction between 30 S ribosomal components in a viomycin resistant mutant of Mycobacterium smegmatis.

A high level viomycin resistant mutant of Mycobacterium smegmatis ATCC 14468 (AC16) was analyzed genetically and biochemically in an attempt to understand the mechanisms of expression of high level viomycin resistance and co-resistance to kanamycin and streptomycin. Genetic analysis has shown that at least three different genes (vicC, str, and kan) were involved in the phenotypic expression of drug resistance in AC16, and high level resistance to viomycin was due to interactions between the products of these genes.

Chemical Phenomena↗

PubMed2005

Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis.

Capreomycin, kanamycin, amikacin, and viomycin are drugs that are used to treat multidrug-resistant tuberculosis. Each inhibits translation, and cross-resistance to them is a concern during therapy. A recent study revealed that mutation of the tlyA gene, encoding a putative rRNA methyltransferase, confers capreomycin and viomycin resistance in Mycobacterium tuberculosis bacteria. Mutations in the 16S rRNA gene (rrs) have been associated with resistance to each of the drugs; however, reports of cross-resistance to the drugs have been variable. We investigated the role of rrs mutations in capreomycin resistance and examined the molecular basis of cross-resistance to the four drugs in M. tuberculosis laboratory-generated mutants and clinical isolates. Spontaneous mutants were generated to the drugs singularly and in combination by plating on medium containing one or two drugs. The frequencies of recovery of the mutants on single- and dual-drug plates were consistent with single-step mutations. The rrs genes of all mutants were sequenced, and the tlyA genes were sequenced for mutants selected on capreomycin, viomycin, or both; MICs of all four drugs were determined. Three rrs mutations (A1401G, C1402T, and G1484T) were found, and each was associated with a particular cross-resistance pattern. Similar mutations and cross-resistance patterns were found in drug-resistant clinical isolates. Overall, the data implicate rrs mutations as a molecular basis for resistance to each of the four drugs. Furthermore, the genotypic and phenotypic differences seen in the development of cross-resistance when M. tuberculosis bacteria were exposed to one or two drugs have implications for selection of treatment regimens.

Amikacin↗

PubMed1997

Molecular analysis of kanamycin and viomycin resistance in Mycobacterium smegmatis by use of the conjugation system.

We examined the molecular mechanisms of resistance to kanamycin and viomycin in Mycobacterium smegmatis. All of the M. smegmatis strains with high-level kanamycin resistance had a nucleotide substitution from A to G at position 1389 of the 16S rRNA gene (rrs). This position is equivalent to position 1408 of Escherichia coli, and mutation at this position is known to cause aminoglycoside resistance. Mutations from G to A or G to T at position 1473 of the M. smegmatis rrs gene were found in viomycin-resistant mutants which had been designated vicB mutants in our earlier studies. Using the M. smegmatis conjugation system, we confirmed that these mutations indeed contributed to kanamycin and viomycin resistance, and kanamycin susceptibility was dominant over resistance in a heterogenomic strain. Additional experiments showed that three of four Mycobacterium tuberculosis strains with high-level kanamycin resistance had a mutation from A to G at position 1400, which was equivalent to position 1389 of M. smegmatis.

Base Sequence↗

PubMed1976

Effect of viomycin on dihydrostreptomycin binding to bacterial ribosomes.

Viomycin, a peptide antibiotic, reduced the amounts of dihydrostreptomycin bound to ribosomes of Myobacterium smegmatis and Escherichia coli, although they have different modes of action. The [3H]dihydrostreptomycin binding to ribosomes could not exchanged with streptomycin or dihydrostreptomycin, but not with unrelated antibiotics, namely, kanamycin, neomycin, spectinomycin, capreomycin, tuberactinomycin-N, chloramphenicol and erythromycin. We suggest that there is a significant interaction between the binding sites of viomycin and streptomycin on ribosomes.

Anti-Bacterial Agents↗

PubMed1990

Similarities and differences in the inhibition patterns of thiostrepton and viomycin: evidence for two functionally different populations of P sites when occupied with AcPhe-tRNA.

According to the allosteric three-site model for the ribosomal elongation cycle, the reactions from the pre- to the post-translocational state and vice versa represent allosteric transitions which are catalyzed by elongation factor (EF)-G and EF-Tu, respectively. It has been shown recently that the non-related antibiotics thiostrepton and viomycin inhibit protein biosynthesis via a surprisingly similar mechanism. Both drugs primarily block the allosteric transitions in either direction (Hausner et al. (1988) J. Biol. Chem. 263, 13103-13111). Here we show that the secondary effects of these antibiotics differ strikingly. When the P site of poly(U) programmed ribosomes is quantitatively filled with AcPhe-tRNA, thiostrepton stimulates the rate of the formation of AcPhe-puromycin 2-fold, whereas viomycin inhibits the puromycin reaction (up to 75% inhibition). The thiostrepton-dependent stimulation is only observed when the drug is given before the P site is occupied; when thiostrepton is added after pre-filling the P site, the peptidyltransferase activity is not affected, in contrast to the translocation reaction, which is blocked irrespective of whether the drug is administered before or after tRNA is bound. The effects of both drugs became distinctly more pronounced when the P sites were saturated with AcPhe-tRNA as compared to half-saturated ribosomes. We conclude that roughly one half of the ribosomes, which first bind AcPhe-tRNA to the P site, carry this ligand in a different orientation to that of the second half of the ribosome population. These two populations probably reflect the P site in the pre- and post-translocational state, respectively.

Allosteric Regulation↗

PubMed1980

Resistance to the antibiotics viomycin and capreomycin in the Streptomyces species which produce them.

Viomycin capreomycin, antibiotics produced by Streptomyces vinaceus and S. capreolus respectively, are potent inhibitors of bacterial protein synthesis. Although these organisms are highly tolerant of their own products in vivo, their ribosomes are fully sensitive to the action of the drugs in vitro. However, they processes novel, antibiotic-inactivating enzymes (viomycin phosphotransferase, capreomycin phosphotransferase, capreomycin acetyltransferase) which, in addition to possible biosynthetic roles, may contribute to the resistances observed in vivo.

Alkaline Phosphatase↗