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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, respo ...
. 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 Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
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. Bacte ...
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 polypept ...
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 Traditional ...
, 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 again ...
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

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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, van ...
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 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 ...
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. T ...
and
Tigecycline Tigecycline, sold under the brand name Tygacil, is an tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resist ...
(a
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 media ...
related to tetracyclines) block the A site on the ribosome, preventing the binding of
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 polypept ...
s.


Proofreading

*
Aminoglycosides 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 ...
, among other potential mechanisms of action, interfere with the
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 Traditional ...
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 injection into a vein, it is used to treat meningitis, plague, cholera, a ...
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 Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. *
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. Macro ...
(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 Quinupristin/dalfopristin, or quinupristin-dalfopristin, (pronunciation: kwi NYOO pris tin / dal FOE pris tin) (trade name Synercid) is a combination of two antibiotics used to treat infections by staphylococci and by vancomycin-resistant '' Ente ...
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. A p ...
, 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 ce ...
, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes. *
Trichothecene The trichothecenes are a large family of chemically related mycotoxins. They are produced by various species of ''Fusarium'', ''Myrothecium'', ''Trichoderma''/''Podostroma'', '' Trichothecium'', ''Cephalosporium'', '' Verticimonosporium'', and '' ...
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. Macrol ...
s,
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 infec ...
Wisteria Lane cases --> CLINDAMYCIN
University of Michigan. Retrieved on July 31, 2009
and
aminoglycosides 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 ...
(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 f ...
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) through t ...
) from the
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
. *
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 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 ribosoma ...
of the eukaryotic 60S ribosomal subunit.


Termination

*
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. Macro ...
and
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 infec ...
(both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome. *
Puromycin Puromycin is an antibiotic protein synthesis inhibitor which causes premature chain termination during translation. Inhibition of translation Puromycin is an aminonucleoside antibiotic, derived from the '' Streptomyces alboniger'' bacterium, ...
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

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Retapamulin Retapamulin is a topical antibiotic developed by GlaxoSmithKline. It is the first drug in the new class of pleuromutilin antibiotics to be approved for human use. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamu ...
Drugbank.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
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
: *
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 *
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 ...
The following antibiotics bind to the 50S ribosomal subunit: *
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 injection into a vein, it is used to treat meningitis, plague, cholera, a ...
*
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 infec ...
*
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, van ...
(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 are ...
) *
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. Macro ...
*
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 ...
* Streptogramins *
Retapamulin Retapamulin is a topical antibiotic developed by GlaxoSmithKline. It is the first drug in the new class of pleuromutilin antibiotics to be approved for human use. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamu ...


See also

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Protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
*
Bacterial translation 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 ...
*
Eukaryotic translation Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping. Initiation Translation initiation is the pr ...
*
Archaeal translation Archaeal translation is the process by which messenger RNA is translated into proteins in archaea. Not much is known on this subject, but on the protein level it seems to resemble eukaryotic translation. Most of the initiation, elongation, and ter ...


References

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