Inhibitors of Bacterial Protein Synthesis
The process that underlines the synthesis of proteins by the ribosomal machinery translating the information provided by the cell nucleus is of fundamental importance and remarkably fascinating. Although the general aspects of the mechanism are universal, the process that occurs in the bacterial cells and the biological element that that are involved are sufficiently different from mammalian protein synthesis offering an opportunity to identify molecules that intefere selectively with the bacterial targets as is required for achieveing a therapeutically useful antimicrobial agents. The main difference involves the actual structure of the ribosome ant ancillary elements in both protein and RNA components.
In order to understand how the various inhibitors of protein synthesis work it is important to be familiar with the main features of the process. The first step is the formation of an initiation complex, that is constituted by a messenger RNA (mRNA), transcribed from the appropriate DNA fragment on a chromosome, the two ribosomal subunits, and methionyl transfer RNA (tRNA) (N-formylated in bacteria) which occupies the peptidyl donor site (P site) on the larger ribosomal subunit. The aminoacyl tRNA matching the next codon to be read binds to the aminoacyl acceptor site (A site), and an enzyme called peptidyl transferase make a bond between the methionine and the new amino acid with the formation of a peptide bond. The mRNA and the ribosome now move with respect to one another so that the dipeptide is translocated from the A to the P site and the next codon of the mRNA is aligned with the A site in preparation for the next aminoacyl tRNA. The process continues to build up amino acids in the nascent peptide chain according to the order dictated by mRNA until a nonsense codon which signals chain termination, is reached.
Colors: The large ribosome subunit is cyan, the small ribosome subunit pale yellow, EF-Tu red,
and EF-G blue. tRNAs are gray (free or complexed with EF-Tu), magenta (binding at A site), green
(in P site), yellow or brown
(in the process of exiting).
The selective activity of therapeutically useful
inhibitors of protein synthesis is not absolute. Some antibiotics, such as
tetracyclines and clindamycin, have sufficient activity against eukaryotic
ribosomes to be of value against certain protozoa. Moreover, also the
mitochondria of mammalian and other eukaryotic cells carry out protein synthesis
and are susceptible to some antibiotics. The selectivity is a combination
of structural differences in the ribosomal targets, access to, and affinity for,
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