the majority of antibiotics that block bacterial protein synthesis ..
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 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.
bacterial protein synthesis inhibitors Study ..
Brandi L, Lazzarini A, Cavaletti L et al. (2006b) Novel tetrapeptide inhibitors of bacterial protein synthesis produced by a Streptomyces sp. Biochemistry 45: 3692–3702.
The initiation phase is the rate‐limiting step in protein synthesis where messenger ribonucleic acid (mRNA), initiator‐transfer RNA (tRNA) and ribosomal subunits are assembled together in the presence of specific initiation factors. This process is the target for a diverse subset of antibiotics that inhibit the initiation step in a variety of different ways. Dissecting the mechanism of action of these antibiotics has provided insight not only into their inhibitory action but also into the process of translation initiation itself. With the dramatic increase in resistance of bacterial strains to many clinically relevant antibiotics, the discovery of improved inhibitors is becoming more important. Because the known initiation inhibitors bind to distinct regions of the ribosome compared with clinically used antibiotics, revisiting the initiation inhibitors may open new avenues to the development of novel antimicrobial agents.