PROTEIN SYNTHESIS

Protein Synthesis

Antibiotics that directly disrupt the processes involved in the synthesis of proteins are known as protein synthesis inhibitors, and act at the ribosome level. Due to the difference between prokaryotic and eukaryotic ribosome structures, some protein synthesis inhibitors are able to damage bacterial cells while leaving human cells unaffected.

Ribosomes are present within all living cells, facilitating protein synthesis (translation) by linking amino acids together. They consist of two components:

A small subunit called 30s which reads the RNA, ensuring the ribosome starts translation at the correct location.

A large subunit called 50s, composed of proteins and ribosomal RNA (rRNA), which form secondary and tertiary structures to maintain structure and carry out catalytic functions of the ribosome.

The primary process that protein synthesis inhibitors attack involve the prokaryotic mRNA translation into proteins, such as initiation, formation and elongation.

Figure 1. A bacterial ribosome facilitating protein synthesis (translation) by linking amino acids together.

Examples of Protein synthesis Inhibitors and their targets

Initiation:

Linezolid disrupts the first step of protein synthesis by preventing the initial complex of the ribosomal subunits, tRNA and mRNA forming (Roger et al. 2018).

Ribosome assembly:

Aminoglycosides bind to the prokaryotic 30s ribosomal subunit, thereby preventing ribosome assembly (Mehta et al., 2003).

Aminoacyl tRNA entry:

Tetracyclines prevent the binding of aminoacyl tRNAs by blocking the A site on the ribosome (Chukwudi, 2016).

Proofreading:

Aminoglycosides interrupt the proofreading process, resulting in an increased rate of error of synthesis and premature termination (Krause, 2016).

Peptidyl transfer:

Chloramphenicol blocks elongation on the 50s ribosomal subunit by inhibiting peptidyl transferase activity, specifically peptide bond formation (Schifano et al.).

Termination:

Macrolides and clindamycin are thought to induce premature dissociation of the peptidyl-tRNA from the ribosome by preventing peptidyltransferase from adding the growing peptide to the next amino acid (Tenson, 2003).

References

Chukwudi CU (2016) rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines. Antimicrob Agents Chemother. 2016;60(8):4433-4441.

Krause KM, Serio AW, Kane TR, Connolly LE (2016) Aminoglycosides: An Overview. Cold Spring Harb Perspect Med. 2016;6(6).

Mehta R, Champney WS (2003) Neomycin and Paromomycin Inhibit 30S Ribosomal Subunit Assembly in Staphylococcus aureus. Current Microbiology. 47 (3): 237–43.

Roger C, Roberts JA, Muller L (2018) Clinical Pharmacokinetics and Pharmacodynamics of Oxazolidinones. Clinical Pharmacokinetics. 57 (5): 559–575.

Schifano JM, Edifor R, Sharp JD, et al. (2013) Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site. Proceedings of the National Academy of Sciences of the United States of America. 110 (21): 8501–6.

Tenson T, Lovmar M, Ehrenberg M (2003) The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J. Mol. Biol. 330 (5): 1005–1014.