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 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. 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 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 synthesizes RNA from a DNA template.
Using the enzyme helicase, RNAP locally opens th ...
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, v ...
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 re ...
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
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 resistance, namely resistance mediated by acquired efflux pumps and/or r ...
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 re ...
, 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, chole ...
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 used ...
.
*
Macrolides (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 ''Entero ...
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. Ma ...
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 in ...
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 re ...
[ (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) 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 fo ...
.
* 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 bo ...
inhibits elongation by enzymatically
Enzymes () are proteins that act as biological catalysts 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 products. A ...
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 ribos ...
of the eukaryotic 60S ribosomal subunit.
Termination
* Macrolides 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 in ...
[ (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 ...
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.
*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
*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.
Retapamul ...
[Drugbank.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
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 fo ...
:
*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, chole ...
[
*]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 in ...
[
*]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, v ...
[ (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[
* Telithromycin][
*]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[
*]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.
Retapamul ...
[
]
See also
* 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
* Eukaryotic translation
* Archaeal translation
References
{{Protein synthesis inhibitor antibiotics
Protein biosynthesis
Protein synthesis inhibitor antibiotics