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British Medical Journal Feb 1954
Topics: Tuberculosis; Viomycin
PubMed: 13115734
DOI: No ID Found -
Tetrahedron Letters Feb 1969
Topics: Chemical Phenomena; Chemistry; Viomycin
PubMed: 4307473
DOI: 10.1016/s0040-4039(01)87723-6 -
Proceedings of the National Academy of... Jan 2016Viomycin is a tuberactinomycin antibiotic essential for treating multidrug-resistant tuberculosis. It inhibits bacterial protein synthesis by blocking elongation factor...
Viomycin is a tuberactinomycin antibiotic essential for treating multidrug-resistant tuberculosis. It inhibits bacterial protein synthesis by blocking elongation factor G (EF-G) catalyzed translocation of messenger RNA on the ribosome. Here we have clarified the molecular aspects of viomycin inhibition of the elongating ribosome using pre-steady-state kinetics. We found that the probability of ribosome inhibition by viomycin depends on competition between viomycin and EF-G for binding to the pretranslocation ribosome, and that stable viomycin binding requires an A-site bound tRNA. Once bound, viomycin stalls the ribosome in a pretranslocation state for a minimum of ∼ 45 s. This stalling time increases linearly with viomycin concentration. Viomycin inhibition also promotes futile cycles of GTP hydrolysis by EF-G. Finally, we have constructed a kinetic model for viomycin inhibition of EF-G catalyzed translocation, allowing for testable predictions of tuberactinomycin action in vivo and facilitating in-depth understanding of resistance development against this important class of antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Dose-Response Relationship, Drug; Guanosine Triphosphate; Peptide Elongation Factor G; Probability; Protein Biosynthesis; Ribosomes; Viomycin
PubMed: 26755601
DOI: 10.1073/pnas.1517541113 -
Rassegna Medica Sarda 1951
Topics: Viomycin
PubMed: 14854253
DOI: No ID Found -
The Journal of Antibiotics. Ser. B Apr 1962
Topics: Viomycin
PubMed: 14039625
DOI: No ID Found -
Clinica Nuova; Rassegna Del Progresso...
Topics: Viomycin
PubMed: 14936260
DOI: No ID Found -
Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans.Chembiochem : a European Journal of... Jan 2009Viomycin and capreomycin are members of the tuberactinomycin family of antituberculosis drugs. As with many antibacterial drugs, resistance to the tuberactinomycins is...
Viomycin and capreomycin are members of the tuberactinomycin family of antituberculosis drugs. As with many antibacterial drugs, resistance to the tuberactinomycins is problematic in treating tuberculosis; this makes the development of new derivatives of these antibiotics to combat this resistance of utmost importance. To take steps towards developing new derivatives of this family of antibiotics, we have focused our efforts on understanding how these antibiotics are biosynthesized by the producing bacteria so that metabolic engineering of these pathways can be used to generate desired derivatives. Here we present the heterologous production of viomycin in Streptomyces lividans 1326 and the use of targeted-gene deletion as a mechanism for investigating viomycin biosynthesis as well as the generation of viomycin derivatives. Deletion of vioQ resulted in nonhydroxylated derivatives of viomycin, while strains lacking vioP failed to acylate the cyclic pentapeptide core of viomycin with beta-lysine. Surprisingly, strains lacking vioL produced derivatives that had the carbamoyl group of viomycin replaced by an acetyl group. Additionally, the acetylated viomycin derivatives were produced at very low levels. These two observations suggested that the carbamoyl group of the cyclic pentapeptide core of viomycin was introduced at an earlier step in the biosynthetic pathway than previously proposed. We present biochemical evidence that the carbamoyl group is added to the beta-amino group of L-2,3-diaminopropionate prior to incorporation of this amino acid by the nonribosomal peptide synthetases that form the cyclic pentapeptide cores of both viomycin and capreomycin.
Topics: Amino Acids; Antitubercular Agents; Bacterial Proteins; Gene Deletion; Multigene Family; Streptomyces lividans; Viomycin
PubMed: 19105177
DOI: 10.1002/cbic.200800646 -
American Review of Tuberculosis Jan 1951
Topics: Anti-Bacterial Agents; Mycobacterium; Mycobacterium tuberculosis; Viomycin
PubMed: 14799783
DOI: 10.1164/art.1951.63.1.1 -
The Journal of Antimicrobial... May 1995Peptidyl-transfer RNA normally dissociates at a low rate from the ribosomes of Escherichia coli during protein synthesis but accumulates under nonpermissive conditions...
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.
Topics: Drug Combinations; Erythromycin; Escherichia coli; RNA, Transfer; RNA, Transfer, Amino Acyl; Viomycin
PubMed: 7592172
DOI: 10.1093/jac/35.5.593 -
Nature Structural & Molecular Biology Jun 2007During protein synthesis, transfer RNA and messenger RNA undergo coupled translocation through the ribosome's A, P and E sites, a process catalyzed by elongation factor... (Comparative Study)
Comparative Study
During protein synthesis, transfer RNA and messenger RNA undergo coupled translocation through the ribosome's A, P and E sites, a process catalyzed by elongation factor EF-G. Viomycin blocks translocation on bacterial ribosomes and is believed to bind at the subunit interface. Using fluorescent resonance energy transfer and chemical footprinting, we show that viomycin traps the ribosome in an intermediate state of translocation. Changes in FRET efficiency show that viomycin causes relative movement of the two ribosomal subunits indistinguishable from that induced by binding of EF-G with GDPNP. Chemical probing experiments indicate that viomycin induces formation of a hybrid-state translocation intermediate. Thus, viomycin inhibits translation through a unique mechanism, locking ribosomes in the hybrid state; the EF-G-induced 'ratcheted' state observed by cryo-EM is identical to the hybrid state; and, since translation is viomycin sensitive, the hybrid state may be present in vivo.
Topics: Fluorescence Resonance Energy Transfer; Models, Molecular; Peptide Elongation Factor G; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA, Messenger; RNA, Transfer; Ribosome Subunits; Viomycin
PubMed: 17515906
DOI: 10.1038/nsmb1243