A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respondi ...

. While a broad interpretation of this definition could be used to describe nearly any compound depending on concentration, in practice, it usually refers to compounds that act at the molecular level on translational machinery (either the ribosome itself or the translation factor), taking advantages of the major differences between

prokaryotic A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...

and

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

ribosome structures.

Mechanism

In general, protein synthesis inhibitors work at different stages of bacterial mRNA translation into proteins, like initiation, elongation (including

aminoacyl tRNA Aminoacyl-tRNA (also aa-tRNA or charged tRNA) is tRNA to which its cognate amino acid is chemically bonded (charged). The aa-tRNA, along with particular elongation factors, deliver the amino acid to the ribosome for incorporation into the polypep ...

entry,

proofreading Proofreading is the reading of a galley proof or an electronic copy of a publication to find and correct reproduction errors of text or art. Proofreading is the final step in the editorial cycle before publication. Professional Tradition ...

peptidyl transfer The peptidyl transferase is an aminoacyltransferase () as well as the primary enzymatic function of the ribosome, which forms peptide bonds between adjacent amino acids using tRNAs during the translation process of protein biosynthesis. The su ...

, and

bacterial translocation Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows ...

) and termination:

Earlier stages

* Rifamycin inhibits bacterial DNA transcription into mRNA by inhibiting DNA-dependent

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...

by binding its beta-subunit. * alpha-Amanitin is a powerful inhibitor of eukaryotic DNA transcription machinery.

Initiation

Linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vanco ...

acts at the initiation stage, probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.

Ribosome assembly

* Aminoglycosides prevent ribosome assembly by binding to the bacterial

30S ribosomal subunit The prokaryotic small ribosomal subunit, or 30 S subunit, is the smaller subunit of the 70S ribosome found in prokaryotes. It is a complex of the 16S ribosomal RNA (rRNA) and 19 proteins. This complex is implicated in the binding of transfer RN ...

Aminoacyl tRNA entry

Tetracyclines Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of ''Streptomyces'' bacteria or produced semi-synthetically from those isolated compounds. T ...

and Tigecycline (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of

Proofreading

* Aminoglycosides, among other potential mechanisms of action, interfere with the

process, causing increased rate of error in synthesis with premature termination.

Peptidyl transfer

Chloramphenicol Chloramphenicol is an antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medica ...

blocks the

step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria. *

Macrolides The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. M ...

(as well as inhibiting ''ribosomal translocation''Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents
Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009 and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting ''peptidyl transfer''. * Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin, as well as inhibiting ''peptidyl transfer''.Page 212
in: Title: Hugo and Russell's pharmaceutical microbiology Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman Edition: 7, illustrated Publisher: Wiley-Blackwell, 2004 Length: 481 pages Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides ...

, as well as causing incomplete chains to be released. *

Geneticin G418 (Geneticin) is an aminoglycoside antibiotic similar in structure to gentamicin B1. It is produced by ''Micromonospora rhodorangea''. G418 blocks polypeptide synthesis by inhibiting the elongation step in both prokaryotic and eukaryotic cel ...

, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes. * Trichothecene mycotoxins are potent and non selective inhibitors of peptide elongation.

Ribosomal translocation

Macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. M ...

clindamycin Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (middle ear infe ...

Wisteria Lane cases --> CLINDAMYCIN
University of Michigan. Retrieved on July 31, 2009 and aminoglycosides (with all these three having other potential mechanisms of action as well), have evidence of inhibition of ribosomal translocation. * Fusidic acid prevents the turnover of elongation factor G (

EF-G EF-G (elongation factor G, historically known as translocase) is a prokaryotic elongation factor involved in protein translation. As a GTPase, EF-G catalyzes the movement (translocation) of transfer RNA (tRNA) and messenger RNA (mRNA) thro ...

) from the ribosome. *

Ricin Ricin ( ) is a lectin (a carbohydrate-binding protein) and a highly potent toxin produced in the seeds of the castor oil plant, ''Ricinus communis''. The median lethal dose (LD50) of ricin for mice is around 22 micrograms per kilogram of bod ...

inhibits elongation by enzymatically modifying an

rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from riboso ...

of the eukaryotic 60S ribosomal subunit.

Termination

and

(both also having other potential mechanisms) cause premature dissociation of the

peptidyl-tRNA Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria. Initiation Initiation of translation in bacteria involves the assembly of the components of the translation system, which are: the two ribosomal s ...

from the ribosome. * Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Thus, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis. *

Streptogramin Streptogramins are a class of antibiotics. Streptogramins are effective in the treatment of vancomycin-resistant ''Staphylococcus aureus'' (VRSA) and vancomycin-resistant ''Enterococcus'' (VRE), two of the most rapidly growing strains of multidru ...

s also cause premature release of the peptide chain.

Protein synthesis inhibitors of unspecified mechanism

* RetapamulinDrugbank.ca > Showing drug card for Retapamulin (DB01256)
Update Date: 2009-06-23 * Mupirocin * Fusidic acid

Binding site

The following antibiotics bind to the 30S subunit of the ribosome: *

Aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ( sugar). The term can also refer ...

s *

The following antibiotics bind to the 50S ribosomal subunit: *

Clindamycin Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (middle ear infe ...

(an

oxazolidinone 2-Oxazolidone is a heterocyclic organic compound containing both nitrogen and oxygen in a 5-membered ring. Oxazolidinones Evans auxiliaries Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. In chemistry, they ar ...

) *

Telithromycin Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug ...

s * Retapamulin

References

{{Protein synthesis inhibitor antibiotics Protein biosynthesis Protein synthesis inhibitor antibiotics