Inhibitors of Protein Synthesis

Inhibitors of Protein synthesis

• Protein synthesis is mainly blocked during the
initiation, elongation or termination due to the
activity of inhibitors like antibiotics as following
Mode of action Antibiotic family Agents

By binding with 30s Aminoglycoside Neomycin, Amikacin, Gentamycin,

Kanamycin, Spectinomycin,
ribosomal subunit Streptomycin, Tobramycin

Tetracyclin & Chlortetracycline, Tetracycline,

Glycylcycline Demeclocycline, Doxycycline,
Minocycline, Tigecycline

By binding with 50s Oxazolidinone Linezolid, Tedizolid phosphate

ribosomal subunit
Amphenicol Chloramphenicol, Azidamfenicol

Pleuromutilin Retapamulin

Macrolide Azithromycin, Clarithromycin,

Erythromycin, Fidaxomicin
 Inhibitors of Protein synthesis
Mode of action Antibiotic family Agents

By binding with Ketolide Telithromycin

50s ribosomal
subunit Lincosamide Clindamycin, Lincomycin

Streptogramin Pristinamycin,
Quinupristin/Dalfopristin
 Aminoglycoside
• Mechanism of action:
• The antibiotic binds to aminoacyl site of 16s rRNA
within 30s ribosomal subunit, leading to misreading
of genetic code & inhibition of translation.
• Usage- against Aerobic Gram-ve bacteria
(Acinetobacter, Enterobacter, haemophilus
influenza, Neisseria gonorrhoeae, Pseudomonas
aeruginosa, Serratia)& Gram +ve bacteria
(Staphylococcus aureus, Pneumococci, Streptococci,
Enterococci, Mycobacteria)
At low concentrations, streptomycin induces the ribosome to
characteristically misread mRNA: One pyrimidine may be mistaken
for the other in the first and second codon positions, and either
pyrimidine may be mistaken for adenine in the first position. This
inhibits the growth of susceptible cells but does not kill them. At
higher concentrations, however, streptomycin prevents proper
chain initiation and thereby causes cell death.
 Tetracycline & G
• The tetracyclines enter the bacterial cell wall in two ways:
passive diffusion and an energy-dependent active transport
system, which is probably mediated in a pH-dependent
fashion.
• Once inside the cell, tetracyclines bind reversibly to the 30S
ribosomal subunit at a position that blocks the binding of the
aminoacyl-tRNA to the acceptor site or A-siteon the mRNA-
ribosome complex. Protein synthesis is ultimately inhibited
leading to a bacteriostatic effect.
• Tigecycline is a derivative of minocycline (9-t-butylglycylamido
minocycline), and while not classified as a tetracycline, it may
share some class-associated adverse effects.  Tigecycline, a
glycylcycline antibiotic, binds to the 30S ribosomal subunit of
susceptible bacteria, thereby inhibiting protein synthesis
It binds to the small subunit of prokaryotic ribosomes.
Tetracycline binding prevents the entry of aminoacyl–tRNAs
into the A site but allows EF-Tu to hydrolyze its GTP. As a
result, protein synthesis cannot proceed, and GTP hydrolysis,
which occurs every time another aminoacyl–tRNA attempts
to enter the ribosome, presents an enormous energetic drain
on the cell.
• The tetracyclines and tigecycline are considered
broad-spectrum bacteriostatic antibiotics that are
used to treat infection caused by many gram-
positive and gram-negative bacteria and many
atypical pathogens.
 Oxazolidinones
• Linezolid is a synthetic antibacterial agent of the
oxazolidinones. Linezolid binds to a site on the
bacterial 23S ribosomal RNA of the 50S subunit and
prevents the formation of a functional 70S initiation
complex, which is an essential component of the
bacterial translation process.
• Linezolid is bacteriostatic against enterococci and
staphylococci
 Amphenicols and Pleuromutilins
• Amphenicols are a class of antibiotics with a
phenylpropanoid structure. Amphenicols are bacteriostatic
by inhibiting protein synthesis.
• They prevent protein chain elongation by inhibiting the
peptidyl transferase activity of the bacterial ribosome.
• It specifically binds to A2451 and A2452 residues in the 23S
rRNA of the 50S ribosomal subunit thus preventing
• The pleuromutilin class of antibiotics has a unique mode of
action which involves inhibition of bacterial protein synthesis
at the level of the bacterial 50S ribosome.
• It binds to domain V of 23S rRNA, inhibits ribosomal
peptidyl transferase activity and partially inhibits the binding
of the initiator tRNA substrate to the ribosomal P-site.
peptide bond formation.
 Macrolides and Ketolides
• Macrolides are antibiotics whose mechanism of
action is primarily bacteriostatic. They bind to the P
site on the 50S subunit of the ribosome, therefore,
inhibiting bacterial protein synthesis. 
• They are believed to do this by:
1. Preventing peptidyltransferase from adding the
growing peptide attached to tRNA to the next
amino acid
2. Inhibiting ribosomal translation or
3. By premature dissociation of the peptidyl-tRNA
from the ribosome
• Ketolides are a class of antibiotics that are
structurally related to the macrolides. Ketolides
block protein synthesis by binding to ribosomal
subunits and may also inhibit the formation of
newly forming ribosomes.
• They are used to treat respiratory tract infections
caused by macrolide-resistant bacteria due to their
ability to bind at two sites at the bacterial ribosome,
as well as, having a structural modification that
makes them poor substrates for efflux pump
mediated resistance.
 Lincosamides
• Lincosamides reversibly bind to 50S ribosomal
subunits preventing peptide bond formation thus
inhibiting bacterial protein synthesis. These
therapeutic agents are bacteriostatic or bactericidal
depending on drug concentration, infection site and
organism.
 Streptogramins
• Quinupristin and Dalfopristin are protein synthesis
inhibitors in a synergistic manner. While each of the
two is only a bacteriostatic agent, the combination
shows bactericidal activity.
• Quinupristin binds to a nearby site on the 50S
ribosomal subunit and prevents elongation of the
polypeptide, as well as, causing incomplete chains to
be released.
• Dalfopristin binds to the 23S portion of the 50S
ribosomal subunit thus changing the conformation of
it, enhancing the binding of Quinupristin by a factor
of about 100. In addition, it inhibits peptidyl transfer. 
 puromycin
• It resembles the 3’ end of Tyr–tRNA.
• Puromycin binds to the ribosomal A site without the
need of elongation factors. The transpeptidation
reaction yields a peptidyl puromycin in which
puromycin’s “amino acid residue” is linked to its
“tRNA” via an amide rather than an ester bond.
• The ribosome therefore cannot catalyze further
transpeptidation, and polypeptide synthesis is
aborted.
 Ricin
• Ricin is an N-glycosidase from castor beans, the
source of castor oil. The enzyme inactivates the
large subunit of eukaryotic ribosomes by
hydrolytically removing the adenine base of a highly
conserved residue of 28S rRNA.
• The modified ribosome is unable to bind elongation
factors, and translation ceases. Because it acts
catalytically, a single ricin molecule can inactivate
tens of thousands of ribosomes.