Ribosomes antibiotic actions

Figure 29.34. Antibiotic Action of Puromycin. Puromycin resembles the aminoacyl terminus of an aminoacyl-tRNA. Its amino group joins the carbonyl group of the growing polypeptide chain to form an adduct that dissociates from the ribosome. This adduct is stable because puromycin has an amide (shown in red) rather than an ester linkage.

L. Belova, T. Tenson, L. Xiong, P.M. McNicholas, and A.S. Mankin. 2001. A novel site of antibiotic action in the ribosome Interaction of evemimicin with the large ribosomal subunit Proc. Natl. Acad. Sci. USA 98 3726-3731. (PubMed) (Full Text in PMC)... 

A satisfactory correlation has been found to exist between sensitivity of archaeal ribosomes to certain antibiotics (streptomycin, erythromycin, a-sarcin) and possession of the specific structural motifs that are involved in antibiotic action. 

Brodersen DE, Clemons WM, Carter AP et al (2000) The structural basis for the action of the antibiotics tetracycline, pactamycin and hygromycin B on the 30S ribosomal subunit. Cell 103 1143-1154... 

Skinner R, E Cundliffe, FJ Schmidt (1983) Site of action of a ribosomal RNA methylase responsible for resistance to erythromycin and other antibiotics. J Biol Chem 258 12702-12706. 

Naturally, if such materials are going to be useful as antibiotic drugs, we require a selective action. We need to be able to inhibit protein biosynthesis in bacteria, whilst producing no untoward effects in man or animals. Although the mechanisms for protein biosynthesis are essentially the same in prokaryotes and eukaryotes, there are some subtle differences, e.g. in the nature of the ribosome and how the process is initiated. Without such differences, the agent would be toxic to man as well as to bacteria. 

Aminoglycosides remain clinically important antibiotics. NMR provided the initial breakthrough in structural understanding of aminoglycoside action on the ribosome, and it remains a powerful tool for the biophysical characterization of drug-RNA interaction. The combined use of NMR, X-ray crystallography, thermodynamic and functional assays, and computational methods is needed to drive forward the development of new aminoglycosides with improved clinical properties. The rich data described above, combined with the application of new synthetic methods, bode well for the future. 

Lincosamides (lincomycin and clindamycin) are representatives of a very small group of drugs synthesized up of an amino acid bound to an amino sugar. Lincosamides bind with the 50 S ribosomal subunit of bacteria and inhibit protein synthesis. They also inhibit pep-tidyltransferase action. Lincosamides are bacteriostatic antibiotics however, when they reach a certain level in the plasma, they also exhibit bactericidal action against some bacteria. Lincosamides are highly active against anaerobic infections such as Peptococcus, Peptostreptococcus, Actinomyces, Propionibacterium, and Clostridium fringens, a few types of Peptococcus and Clostridium. 

Dactinomycin is an antitumor antibiotic isolated from a Streptomyces organism. It binds tightly to double-stranded DNA through intercalation between adjacent guanine-cytosine base pairs and inhibits all forms of DNA-dependent RNA synthesis, with ribosomal RNA formation being most sensitive to drug action. 

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