In the current medical system, the successful application of various antibiotics has proven that bacterial protein synthesis is a suitable target for drug intervention. The emergence of more and more research results on classical protein synthesis inhibitors and ribosomal RNA binding is a reasonable explanation for the selective role of bacteria, and it also explains why relatively rare chromosomal point mutations in most bacteria cause changes in the structure of the target site and consequently resistance. Based on these reliable research results, Creative Biolabs can help customers screen and design some new protein synthesis inhibitors that may be developed as new antibiotics.
An important reason why antibiotic drugs that inhibit protein synthesis have been used on a large scale over the past 100 years is their selective toxicity. These medicinal antibiotics are active against bacteria but not active on eukaryotic cells, which is the basis for their safe use in the human body. The main determinant of this selectivity is the nature of the ribosome class present in each cell type. Prokaryotic cells contain 70S ribosomes, while in eukaryotic cells, the main type of ribosomes is 80S, and 70S particles are present in mitochondria. Differences in ribosome structure not only lead to differences in drug binding sites but also explain selective activity against prokaryotic or eukaryotic cells. Therefore, screening biomolecules that have preferential inhibitory activity on the 70S ribosomal system is generally likely to have sufficiently selective toxicity, and they have the potential for further research as antibacterial agents.
The 70S ribosomes of prokaryotes consist of a small subunit (30S) and a large subunit (50S). The small subunit consists of a 16S rRNA chain and 20 proteins. The large subunit (50S) contains 23S and 5S rRNA proteins. These components interact to convert mRNA into a polypeptide chain through three stages of initiation, extension, and termination. Although other RNA sequences have been explored as potential drug targets in antibiotic screening, bacterial ribosomes are still the only clinically approved antibiotic targets. The reason for this phenomenon is that the ribosome covers a large part of cellular RNA and contains different and well-defined binding sites from small molecules, which is not necessarily common for other RNAs with less structural features.
Our drug screening process shows that even small molecules with only moderate affinities may show practical efficacy due to the large volume of rRNA in the cell and the complex functions of its components. In addition, in terms of the potential of drug development, bacterial ribosomes will slow the evolution of their resistance, because RNA components are usually encoded by multiple operons. This is another reason that makes bacterial ribosomes the most attractive target for antibacterial drugs.
Fig.1 Crystal structure of three tRNA molecules interacting with an mRNA molecule and the 16s rRNA in the 30S ribosome. (McCoy, 2014)
To screen and identify small molecule inhibitors during the translation of prokaryotic cells, Creative Biolabs has established an economical, high-throughput, cell-free protein synthesis screening system based on E. coli lysates. We can help our customers perform a complete synthetic analysis, compared with known antibiotic classes, and further test the inhibition of cell-free protein synthesis by structural analysis. In addition, we can also determine the dose dependence of drug candidates through luciferase activity to provide a reliable reference for the subsequent drug development process.
If you are interested in our antimicrobial development services, you can contact us for more details.
Reference
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