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Tuberactinomycin antibiotics: Biosynthesis, anti-mycobacterial action, and mechanisms of resistance.Frontiers in Microbiology 2022The tuberactinomycins are a family of cyclic peptide ribosome-targeting antibiotics with a long history of use as essential second-line treatments for drug-resistant... (Review)
Review
The tuberactinomycins are a family of cyclic peptide ribosome-targeting antibiotics with a long history of use as essential second-line treatments for drug-resistant tuberculosis. Beginning with the identification of viomycin in the early 1950s, this mini-review briefly describes tuberactinomycin structures and biosynthesis, as well as their past and present application in the treatment of tuberculosis caused by infection with . More recent studies are also discussed that have revealed details of tuberactinomycin action on the ribosome as well as resistance mechanisms that have emerged since their introduction into the clinic. Finally, future applications of these drugs are considered in the context of their recent removal from the World Health Organization's List of Essential Medicines.
PubMed: 36033858
DOI: 10.3389/fmicb.2022.961921 -
British Medical Journal Feb 1954
Topics: Tuberculosis; Viomycin
PubMed: 13115734
DOI: No ID Found -
International Journal of Molecular... Aug 2015Enzymes in the transcarbamylase family catalyze the transfer of a carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate. The two... (Review)
Review
Enzymes in the transcarbamylase family catalyze the transfer of a carbamyl group from carbamyl phosphate (CP) to an amino group of a second substrate. The two best-characterized members, aspartate transcarbamylase (ATCase) and ornithine transcarbamylase (OTCase), are present in most organisms from bacteria to humans. Recently, structures of four new transcarbamylase members, N-acetyl-L-ornithine transcarbamylase (AOTCase), N-succinyl-L-ornithine transcarbamylase (SOTCase), ygeW encoded transcarbamylase (YTCase) and putrescine transcarbamylase (PTCase) have also been determined. Crystal structures of these enzymes have shown that they have a common overall fold with a trimer as their basic biological unit. The monomer structures share a common CP binding site in their N-terminal domain, but have different second substrate binding sites in their C-terminal domain. The discovery of three new transcarbamylases, l-2,3-diaminopropionate transcarbamylase (DPTCase), l-2,4-diaminobutyrate transcarbamylase (DBTCase) and ureidoglycine transcarbamylase (UGTCase), demonstrates that our knowledge and understanding of the spectrum of the transcarbamylase family is still incomplete. In this review, we summarize studies on the structures and function of transcarbamylases demonstrating how structural information helps to define biological function and how small structural differences govern enzyme specificity. Such information is important for correctly annotating transcarbamylase sequences in the genome databases and for identifying new members of the transcarbamylase family.
Topics: Amino Acid Sequence; Carboxyl and Carbamoyl Transferases; Catalysis; Catalytic Domain; Databases, Genetic; Humans; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Sequence Alignment; Substrate Specificity
PubMed: 26274952
DOI: 10.3390/ijms160818836 -
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 -
International Journal of Molecular... Sep 2021The growth of the polypeptide chain occurs due to the fast and coordinated work of the ribosome and protein elongation factors, EF-Tu and EF-G. However, the exact...
The growth of the polypeptide chain occurs due to the fast and coordinated work of the ribosome and protein elongation factors, EF-Tu and EF-G. However, the exact contribution of each of these components in the overall balance of translation kinetics remains not fully understood. We created an in vitro translation system replacing either elongation factor with heterologous thermophilic protein from . The rates of the A-site binding and decoding reactions decreased an order of magnitude in the presence of thermophilic EF-Tu, indicating that the kinetics of aminoacyl-tRNA delivery depends on the properties of the elongation factor. On the contrary, thermophilic EF-G demonstrated the same translocation kinetics as a mesophilic protein. Effects of translocation inhibitors (spectinomycin, hygromycin B, viomycin and streptomycin) were also similar for both proteins. Thus, the process of translocation largely relies on the interaction of tRNAs and the ribosome and can be efficiently catalysed by thermophilic EF-G even at suboptimal temperatures.
Topics: Bacterial Proteins; Escherichia coli; Peptide Chain Elongation, Translational; Peptide Elongation Factor G; Peptide Elongation Factor Tu; RNA, Bacterial; RNA, Transfer; Ribosomes; Thermus thermophilus
PubMed: 34502523
DOI: 10.3390/ijms22179614 -
Frontiers in Chemistry 2024Many enzymes in nature utilize a free arginine (L-Arg) amino acid to initiate the biosynthesis of natural products. Examples include nitric oxide synthases, which... (Review)
Review
Many enzymes in nature utilize a free arginine (L-Arg) amino acid to initiate the biosynthesis of natural products. Examples include nitric oxide synthases, which generate NO from L-Arg for blood pressure control, and various arginine hydroxylases involved in antibiotic biosynthesis. Among the groups of arginine hydroxylases, several enzymes utilize a nonheme iron(II) active site and let L-Arg react with dioxygen and -ketoglutarate to perform either C-hydroxylation, C-hydroxylation, C-hydroxylation, or C-C-desaturation. How these seemingly similar enzymes can react with high specificity and selectivity to form different products remains unknown. Over the past few years, our groups have investigated the mechanisms of L-Arg-activating nonheme iron dioxygenases, including the viomycin biosynthesis enzyme VioC, the naphthyridinomycin biosynthesis enzyme NapI, and the streptothricin biosynthesis enzyme OrfP, using computational approaches and applied molecular dynamics, quantum mechanics on cluster models, and quantum mechanics/molecular mechanics (QM/MM) approaches. These studies not only highlight the differences in substrate and oxidant binding and positioning but also emphasize on electronic and electrostatic differences in the substrate-binding pockets of the enzymes. In particular, due to charge differences in the active site structures, there are changes in the local electric field and electric dipole moment orientations that either strengthen or weaken specific substrate C-H bonds. The local field effects, therefore, influence and guide reaction selectivity and specificity and give the enzymes their unique reactivity patterns. Computational work using either QM/MM or density functional theory (DFT) on cluster models can provide valuable insights into catalytic reaction mechanisms and produce accurate and reliable data that can be used to engineer proteins and synthetic catalysts to perform novel reaction pathways.
PubMed: 38406558
DOI: 10.3389/fchem.2024.1365494 -
British Medical Journal Sep 1968
Topics: Aminosalicylic Acids; Costs and Cost Analysis; Cycloserine; Drug Synergism; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Pyrazinamide; Streptomycin; Thioacetazone; Tuberculosis; Viomycin
PubMed: 4175142
DOI: No ID Found -
Proceedings of the National Academy of... May 2020Viomycin, an antibiotic that has been used to fight tuberculosis infections, is believed to block the translocation step of protein synthesis by inhibiting ribosomal...
Viomycin, an antibiotic that has been used to fight tuberculosis infections, is believed to block the translocation step of protein synthesis by inhibiting ribosomal subunit dissociation and trapping the ribosome in an intermediate state of intersubunit rotation. The mechanism by which viomycin stabilizes this state remains unexplained. To address this, we have determined cryo-EM and X-ray crystal structures of 70S ribosome complexes trapped in a rotated state by viomycin. The 3.8-Å resolution cryo-EM structure reveals a ribosome trapped in the hybrid state with 8.6° intersubunit rotation and 5.3° rotation of the 30S subunit head domain, bearing a single P/E state transfer RNA (tRNA). We identify five different binding sites for viomycin, four of which have not been previously described. To resolve the details of their binding interactions, we solved the 3.1-Å crystal structure of a viomycin-bound ribosome complex, revealing that all five viomycins bind to ribosomal RNA. One of these (Vio1) corresponds to the single viomycin that was previously identified in a complex with a nonrotated classical-state ribosome. Three of the newly observed binding sites (Vio3, Vio4, and Vio5) are clustered at intersubunit bridges, consistent with the ability of viomycin to inhibit subunit dissociation. We propose that one or more of these same three viomycins induce intersubunit rotation by selectively binding the rotated state of the ribosome at dynamic elements of 16S and 23S rRNA, thus, blocking conformational changes associated with molecular movements that are required for translocation.
Topics: Anti-Bacterial Agents; Crystallography, X-Ray; Escherichia coli; Models, Molecular; Molecular Conformation; Protein Binding; Protein Biosynthesis; RNA, Messenger; RNA, Ribosomal; RNA, Transfer; Ribosomal Proteins; Ribosomes; Viomycin
PubMed: 32341159
DOI: 10.1073/pnas.2002888117 -
The EMBO Journal Jan 2000One of the most important families of antibiotics are the aminoglycosides, including drugs such as neomycin B, paromomycin, gentamicin and streptomycin. With the... (Review)
Review
One of the most important families of antibiotics are the aminoglycosides, including drugs such as neomycin B, paromomycin, gentamicin and streptomycin. With the discovery of the catalytic potential of RNA, these antibiotics became very popular due to their RNA-binding capacity. They serve for the analysis of RNA function as well as for the study of RNA as a potential therapeutic target. Improvements in RNA structure determination recently provided first insights into the decoding site of the ribosome at high resolution and how aminoglycosides might induce misreading of the genetic code. In addition to inhibiting prokaryotic translation, aminoglycosides inhibit several catalytic RNAs such as self-splicing group I introns, RNase P and small ribozymes in vitro. Furthermore, these antibiotics interfere with human immunodeficiency virus (HIV) replication by disrupting essential RNA-protein contacts. Most exciting is the potential of many RNA-binding antibiotics to stimulate RNA activities, conceiving small-molecule partners for the hypothesis of an ancient RNA world. SELEX (systematic evolution of ligands by exponential enrichment) has been used in this evolutionary game leading to small synthetic RNAs, whose NMR structures gave valuable information on how aminoglycosides interact with RNA, which could possibly be used in applied science.
Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Design; Humans; Models, Molecular; Nucleic Acid Conformation; Protein Biosynthesis; RNA; RNA-Binding Proteins; Viomycin
PubMed: 10619838
DOI: 10.1093/emboj/19.1.1 -
Frontiers in Microbiology 2022Resistance to tuberculosis (TB) drugs has become a major threat to global control efforts. Early case detection and drug susceptibility profiling of the infecting...
BACKGROUND
Resistance to tuberculosis (TB) drugs has become a major threat to global control efforts. Early case detection and drug susceptibility profiling of the infecting bacteria are essential for appropriate case management. The objective of this study was to determine the drug susceptibility profiles of difficult-to-treat (DTT) TB patients in Ghana.
METHODS
Sputum samples obtained from DTT-TB cases from health facilities across Ghana were processed for rapid diagnosis and detection of drug resistance using the Genotype MTBDR and Genotype MTBDR. from Hain Life science.
RESULTS
A total of 298 (90%) out of 331 sputum samples processed gave interpretable bands out of which 175 (58.7%) were resistant to at least one drug (ANY); 16.8% (50/298) were isoniazid-mono-resistant (INH), 16.8% (50/298) were rifampicin-mono-resistant (RIF), and 25.2% (75/298) were MDR. 24 (13.7%) of the ANY were additionally resistant to at least one second line drug: 7.4% (2 RIF, 1 INH, and 10 MDR samples) resistant to only FQs and 2.3% (2 RIF, 1 INH, and 1 MDR samples) resistant to AMG drugs kanamycin (KAN), amikacin (AMK), capreomycin (CAP), and viomycin (VIO). Additionally, there were 4.0% (5 RIF and 2 MDR samples) resistant to both FQs and AMGs. 81 (65.6%) out of 125 INH-resistant samples including INH and MDR had -mutations (MT) whereas 15 (12%) had -MT. The remaining 28 (22.4%) had both and MT. All the 19 FQ-resistant samples were mutants whereas the 10 AMGs were (3), (3) as well as , and co-mutants (4). Except for the seven pre-XDR samples, no sample had MT.
CONCLUSION
The detection of several pre-XDR TB cases in Ghana calls for intensified drug resistance surveillance and monitoring of TB patients to, respectively, ensure early diagnosis and treatment compliance.
PubMed: 36713197
DOI: 10.3389/fmicb.2022.1069292