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, re ...

. 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 (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

and

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

ribosome structures.

Mechanism

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

proofreading Proofreading is a phase in the process of publishing where galley proofs are compared against the original manuscripts or graphic artworks, to identify transcription errors in the typesetting process. In the past, proofreaders would place corr ...

, peptidyl transfer, and bacterial translocation) and termination:

Earlier stages

Rifamycin The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium '' Amycolatopsis rifamycinica'' or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective aga ...

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 catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...

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, va ...

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

Ribosome assembly

Aminoglycosides Aminoglycoside is a medicinal chemistry, medicinal and bacteriology, bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ...

prevent ribosome assembly by binding to the bacterial 30S ribosomal subunit.

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. ...

and

Tigecycline Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline class drug that is administered intravenously. It was developed in response to the growing ra ...

glycylcycline Glycylcyclines are a class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of Tetracycline#Mechanism and resistance, tetracycline resistance, namely resistance med ...

related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs.

Proofreading

, 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 useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by intravenous, injection into a vein, it is used to treat meningitis, pl ...

blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. *

Macrolides Macrolides are a class of mostly natural products with a large macrocycle, macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural prod ...

(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''. * Streptogramins such as 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. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

, as well as causing incomplete chains to be released. * Geneticin, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes. *

Trichothecene Trichothecenes constitute a large group of chemically related mycotoxins. They are produced by Fungus, fungi of the genera ''Fusarium'', ''Myrothecium'', ''Trichoderma'', ''Podostroma'', ''Trichothecium'', ''Cephalosporium'', ', ''Stachybotrys'' ...

mycotoxins are potent and non selective inhibitors of peptide elongation.

Ribosomal translocation

Macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...

clindamycin Clindamycin is a lincosamide 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 (mi ...

Wisteria Lane cases → CLINDAMYCIN
University of Michigan. Retrieved on July 31, 2009 and

aminoglycosides Aminoglycoside is a medicinal chemistry, medicinal and bacteriology, bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ...

(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 Elongation factors are a set of proteins that function at the ribosome, during protein synthesis, to facilitate translational elongation from the formation of the first to the last peptide bond of a growing polypeptide. Most common elongation ...

G ( EF-G) from the

ribosome Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...

. *

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 body ...

inhibits elongation by

enzymatically An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...

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 ribosomal ...

of the eukaryotic 60S ribosomal subunit.

Termination

and

(both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA 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. * Streptogramins 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 Mupirocin, sold under the brand name Bactroban among others, is a topical antibiotic useful against superficial skin infections such as impetigo or folliculitis. It may also be used to get rid of methicillin-resistant ''S. aureus'' (MRSA) wh ...

* Fusidic acid

Binding site

The following antibiotics bind to the 30S subunit of the

: *

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 a lincosamide 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 (mi ...

(an oxazolidinone) *

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 Dru ...

* Streptogramins * Retapamulin

References

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