BI 397 (formerly A-A-1) is a semisynthetic derivative of the teicoplanin-like glycopeptide A40926. It was more active in vitro against staphylococci (including some teicoplanin-resistant strains) than teicoplanin and vancomycin. Against streptococci (including penicillin-resistant strains) BI 397 has activity comparable with that of teicoplanin and better than vancomycin. BI 397, when administered to rats by the i.v. route, gives high and long lasting blood levels. It shows excellent activity in models of acute septicaemia in immunocompetent and neutropenic mice. In a rat staphylococcal endocarditis model it is as effective as teicoplanin and vancomycin at reducing bacterial loads in the heart, but at lower dosages and with a reduced number of daily treatments compared with the two glycopeptide controls. BI 397 is highly efficacious in clearing penicillin-susceptible and -resistant pneumococci from lungs of immunocompetent and neutropenic rats. The data from these studies show that BI 397 combines an excellent in-vitro antibacterial activity with favourable pharmacokinetic behaviour resulting in potent in-vivo activity.
In the course of a microbial product screening aimed at the discovery of novel antibiotics acting on bacterial protein synthesis, a complex of three structurally related tetrapeptides, namely, GE81112 factors A, B, and B1, was isolated from a Streptomyces sp. The screening was based on a cell-free assay of bacterial protein synthesis driven by a model mRNA containing natural initiation signals. In this study we report the production, isolation, and structure determination of these novel, potent and selective inhibitors of cell-free bacterial protein synthesis, which stably bind the 30S ribosomal subunit and inhibit the formation of fMet-puromycin. They did not inhibit translation by yeast ribosomes in vitro. Spectroscopic analyses revealed that they are tetrapeptides constituted by uncommon amino acids. While GE81112 factors A, B, and B1 were effective in inhibiting bacterial protein synthesis in vitro, they were less active against Gram-positive and Gram-negative bacterial cells. Cells grown in minimal medium were more susceptible to the compounds than those grown in rich medium, and this is most likely due to competition or regulation by medium components during peptide uptake. The novelty of the chemical structure and of the specific mode of action on the initiation phase of bacterial protein synthesis makes GE81112 a unique scaffold for designing new drugs.
Many known antibiotics target the translational apparatus, but none of them can selectively inhibit initiation of protein synthesis and͞or is prokaryotic-specific. This article describes the properties of GE81112, an effective and prokaryotic-specific initiation inhibitor. GE81112 is a natural tetrapeptide produced by a Streptomyces sp. identified by an in vitro high-throughput screening test developed to find inhibitors of the prokaryotic translational apparatus preferentially acting on steps other than elongation. In vivo GE81112 inhibits protein synthesis but not other cell functions such as DNA duplication, transcription, and cell wall synthesis. In vitro GE81112 was found to target the 30S ribosomal subunit and to interfere with both coded and noncoded P-site binding of fMettRNA, thereby selectively inhibiting formation of the 30S initiation complex.30S initiation complex ͉ fMet-tRNA binding ͉ P-site inhibition
GE82832, a secondary metabolite produced by Streptosporangium cinnabarinum (strain GE82832), has been identified as a translational inhibitor by in vitro screening of a library of natural products. Secondary functional tests specific for individual steps of the translational pathway demonstrated that translocation is the specific target of GE82832. Chemical probing in situ demonstrated that this antibiotic protects bases A1324 and A1333 and exposes C1336 of 16S rRNA, thereby indicating that its binding site is located on the head of the 30S ribosomal subunit. The ribosomal location of GE82832, near ribosomal protein S13 and G1338, two elements of the small subunit that are part of or close to the B1a intrasubunit bridge, suggests that translocation inhibition results from an altered dynamics of 30S-50S ribosomal subunit interaction.
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