Protein synthesis inhibitor antibiotics

Fadhel Ahmed Alomar, Ph.D.

Dept. of Pharmacology, College of Clinical Pharmacy, IAU
falomar@iau.edu.sa
General concepts of protein synthesis inhibitor antibiotics

 Bacteria translation to form protein is an important target for many antibiotic

drugs

 The mRNA translation to protein talks place in the ribosomes

 The differences in the structure of ribosome between eukaryotic cells &

prokaryotic cells of microorganisms provide the basis for selective toxicity
of protein synthesis inhibitor antibiotics

 The eukaryotic cells have 80S ribosome that is composed of a small

ribosomal subunit (40S ) & large ribosomal subunit (60S)

 The prokaryotic cells have 70S ribosome that is composed of a small

30S ribosomal subunit & large 50S ribosomal subunit
General concepts of protein synthesis inhibitor antibiotics

 In bacteria, protein synthesis involves two major steps

I. Formation of the initiation complex; includes ribosomal
subunits, mRNA, N-formyl-methionine tRNA)
II. Elongation of peptide chain

 The vast majority of protein synthesis inhibitor antibiotics are

bacteriostatic drugs
 They inhibit the growth or proliferation of microorganisms by
disrupting their protein synthesis during
o Formation of the initiation complex
o Elongation of peptide chain
Translation of mRNA to Protein in bacteria initiation complex
Linezolid binds to 50S
AG block P-site & inhibit
binding the 1ST tRNA
Translation of mRNA to Protein in bacteria Elongation of peptide
Chloramphenicol inhibits Macrolides bind to 50S &
peptidyl transferase inhibit translocation

peptidyl transferase

P site A site
E site

Mupirocin inhibits isoleucyl TCs bind to 30S & inhibit the

transfer RNA synthetase binding the next tRNA
Used to treat MRSA
Protein synthesis inhibitor antibiotics
Classification of protein synthesis inhibitor antibiotics
I. Antibiotics interfere with & inhibits the formation of the initiation
complex
1. Aminoglycosides (bactericidal)
o Gentamicin, streptomycin, amikacin and neomycin
2. Linezolid

II. Antibiotics inhibit the elongation of peptide chain, a.a. incorporation

1. Tetracycline
o Tetracycline, doxacycline and minocycline
2. Macrolides
o Erythromycin, clarithromycin and azithromycin
3. Miscellaneous
o Clindamycin & chloramphenicol
o Streptogramins & mupirocin
Drugs that interfere with & inhibits the
formation of the initiation complex
 Aminoglycosides (AGs)
 Prototype: Gentamicin
 Amikacin, streptomycin & neomycin

 Gentamicin, amikacin & streptomycin are used parenterally

 Neomycin is used locally

 They have long post-antibiotic effects

 Aminoglycoside antibiotics have a narrow margin of safety

 Their bactericidal activities are concentration dependent NOT

related to exposure time (which is responsible for toxicity)

 The more exposure time to AGs, is more likely to cause toxicity
 Aminoglycosides (AGs)
 Therapeutic indications
 They are active against aerobic G -ve organisms & G +ve staph

 They are usually used in combination with β-lactam antibiotic (WHY?)

1. To enhance the penetration of AG into bacterial cells
2. To provide synergistic
3. To prevent the development of resistance to the individual agent
4. To expand the empiric spectrum of activity of the antimicrobial
regimen

 Gentamicin is commonly used in combination with cell wall synthesis

inhibitor antibiotic (e.g ampicillin) to treat infections such as healthcare
associated with pneumonia and sepsis (P. aeruginosa)
 Aminoglycosides (AGs)
 Therapeutic indications
 Gentamycin ophthalmic solution and ointments also available to treat
ocular bacterial infections; conjunctivitis & corneal ulcers

corneal ulcers

 Streptomycin is used with other antimicrobial to treat tuberculosis

 Neomycin is used topically in combination with other agents to treat

infection-induced eczema & diaper rash in fungal skin infections

o Kenacomb ointment: neomycin sulfate (antibacterial agent),

gramicidin (antibacterial agent), nystatin (an antifungal) &
triamcinolone acetonide (FYI)
 Aminoglycosides (AGs)
 Pharmacokinetics
 Highly polar compounds at physiologic pH and their polarity responsible
in part for their pharmacokinetic properties
1. Not absorbed from GIT
2. Do not penetrate into CNS
3. Excreted rapidly by the kidneys

 They diffuse through porins in the out membrane of Gram –ve bacteria
into periplasmic space

 Transport of AGs across the plasma membrane is an oxygen-dependent

active process (active transport system)
o Strict anaerobes are not susceptible to AGs
 Aminoglycosides (AGs)
 M.O.A (Bactericidal; Why )
1. They Inhibit protein translation by locking the first step in initiation
process of translation
 They bind irreversibly to the 30S ribosomal subunit & blocks the P-
site inhibition the binding of the 1st tRNA to mRNA leads
to inhibition of association of 50S ribosomal subunit with mRNA-
30S & formation of 70S initiation complex (70SIC)

2. During elongation; AG (large molecules) bind to 30S ribosomal

mRNA will not fit well causes shift in reading frame of mRNA
causes misreading of genetic codon incorrect incorporation of
amino acids into proteins formation leads to formation a wrong
sequence of a.a non-functional proteins & death of microorganism
 Aminoglycosides (AGs)
 Adverse effects
 25% Ototoxicity (deafness, irreversible) & nephrotoxicity
o S.Es are more related to exposure time (not to conc.); once daily
with high dose is less toxic than three times daily with low doses
o Plasma levels should be monitored to avoid AGs toxicity

 AGs decrease Ach release → potentiate skeletal muscle relaxants

(atracurium) & cause myasthenia gravis-like syndrome & respiratory
paralysis,
o Discontinue administration of Gentamicin(e) immediately
o Neostigmine (a reversible cholinesterase inhibitor) should be
administered to counteract gentamicin-induced respiratory paralysis

 Contraindications (FDA pregnancy category D)

 Pregnancy (cross placenta, teratogenicity & cause neonatal deafness)
Plasma Concentrations (g/ml) after Administration of
5.1 mg/kg of Gentamicin

The threshold for toxicity

 Linezolid
 It is a synthetic bacteriostatic antibiotic & active against serious infections
caused by Gram +ve bacteria that are resistant to other antibiotics

 Has less activity against Gram–negative aerobic and anaerobic bacteria

 It is relatively safe to be used in people of all ages and in people with liver
disease or kidney impairment

 Pharmacokinetics
 Well absorbed orally (bioavailability ~ 100%) & excreted by kidney

 Clinical indications
 The 600 mg intravenously or orally q12 hrs is used to treat severe skin
and pneumonia infections caused streptococci, vancomycin-resistant
enterococci (VRE) and MRSA
 Linezolid
 M.O.A
 Binds to the 50S ribosomal subunit (instead 30S) leads to inhibition of
association of 50S ribosomal subunit with mRNA-30S and preventing
formation of complex (70S), the last step in the initiation process

 Adverse effects
 GI disturbance
 Bone marrow suppression (myelosuppression) & peripheral
neuropathy (Long-term use)
 Fungal infections may also occur as linezolid eradicates normal
bacterial flora
Translation of mRNA to Protein in bacteria-INITIATION
Linezolid binds to 50S
AG block P-site & inhibit
binding the 1ST tRNA
Drugs that inhibit the elongation of peptide
chain
Translation of mRNA to Protein in bacteria-ELONGATION
Chloramphenicol inhibits Macrolides bind to 50S &
peptidyl transferase inhibit translocation

peptidyl transferase

P site A site
E site

Mupirocin inhibits isoleucyl TCs bind to 30S & inhibit the

transfer RNA synthetase binding the next tRNA
Used to treat MRSA
 Tetracyclines (TCs)
 Prototype: Tetracycline
 Doxycycline and minocycline

 Common properties of TCs

 They are bacteriostatic and orally effective

 Widely distributed through body include bone/teeth, placenta, breast

milk & CNS

 Minocycline (QD) & doxycycline (BID) have long antimicrobial activities

compared to tetracycline (QID) which has short duration of action

 Tetracycline forms insoluble chelates with multivalent cations such as

Ca2+ & Mg2+
o Tetracycline should not be administered with dairy products, iron
supplements and antacid preparations
Effect of antacids & milk on the absorption of tetracycline
 Tetracyclines (TCs)
 Therapeutic indications
 They are a broad-spectrum antibiotics & effective against G +ve & G -
ve organisms (H. pylori)
 They are used to chlamydia trachomatis (Atypical bacteria; sexually
transmitted infection)

 Tetracycline is used for treatment …

o Protozoal infection e.g., amoebiasis & malaria
o Typhus (Rickettsia bacteria) & Cholera (Vibrio cholerae)

 Doxycycline is used for anthrax (Bacillus anthracis)

 Minocycline is used orally to treat acne vulgaris

 Tetracyclines
 M.O.A
 Bind to the 30S ribosomal subunit of the ribosome complex during
elongation process leads to inhibition the binding of the next
aminoacyl-tRNA to A-site causing premature termination of protein
biosynthesis
 Tetracyclines
 Adverse effects
 GI tract irritation and photosensitivity
 Vestibular dysfunction (not loss of hearing)- Balance disorder
 Renal toxicity from date expired tetracycline
 May prolong QT interval ( arrhythmias)
 Deposition in the bone and teeth (permanent)
 UV light turns to fluorescence

 Contraindications
 Children under 8 years of age, lactating mother and pregnant women
 Yellow & brown discoloration of fetal teeth
 Bony deformity and growth retardation

 Today, TCs are not widely used replaced by macrolide

 Macrolides
 Prototype: Erythromycin
 Clarithromycin and azithromycin

 Clinical indications
1. They are bacteriostatic antibiotics & active against aerobic & anaerobic
gram-positive cocci
2. Used as a substitute for penicillin in penicillin-sensitive patients

3. They are widely used for upper respiratory infections (H. influenzae) ,
chlamydial & diphtheria (G +ve bacilli)
4. Macrolide antibitics are considered the treatment of choice for atypical
pneumonias infections (mycoplasma pneumonia)
o M. pneumoniae is characterized by the absence of a peptidoglycan
cell wall & causing resistance to many antibacterial medications
 Macrolides
 Pharmacokinetic
 Erythromycin
o ~95% of erythromycin is metabolized by liver & excreted in the bile
o It is administrated every 6 hours

 Clarithromycin
o It is eliminated from body by renal (~ 40%) & the remainder is
excreted via the bile
o It is administrated every 12 hours

 Azithromycin
o ~85% of azithromycin undergoes biliary excretion (~15% excreted
unchanged in the urine )
o Dosage adjustment is not required for renal insufficiency
o It is administrated once daily
 Macrolides
 M.O.A
 They are bacteriostatic antibiotics and act during elongation process
 Macrolides bind to the 50S ribosomal subunit leads to inhibiting the
translocation of ribosome complex & preventing elongation of peptide
resulting in premature termination of protein synthesis

 Adverse effects
 GIT irritation
 Hepatotoxicity (more in erythromycin)
 Fatal cardiac arrhythmias
 Erythromycin & azithromycin (category B) are more safe during
pregnancy compared to clarithromycin (category C)
Miscellaneous drugs that inhibit the elongation
of peptide chain
 1-Clindamycin
 It is bacteriostatic drug and has a broad spectrum antibiotic
activities
 Has activity against many aerobic gram-positive cocci as well as
many anaerobic gram-negative and gram-positive bacteria
 More active than erythromycin & clarithromycin against
anaerobic bacteria

 Pharmacokinetics
 Completely absorbed following oral administration
 Widely distributed in many organs including bone BUT few amount can
cross BBB
 Mainly metabolized by liver & excreted in the urine
 1-Clindamycin
 Therapeutic indications
 It is used orally, topically and parenterally for bacterial infections
due to sensitive organisms
 Orally to treat anaerobic infections, including dental,
respiratory tract and soft tissue infection
 Locally to treat acne (lotion, cream, or gel ) & vaginal
infection ( cream or suppository)

 M.O.A
 As macrolides, clindamycin binds to 50S during elongation of the
nascent peptide chain, blocks the binding of peptidyl-tRNA to
the acceptor site & thus inhibits protein biosynthesis
 1-Clindamycin
 Adverse effects:
 Diarrhea (up to 20%)
 Clostridium Difficile-Associated Diarrhea; is the major concern
that may occur weeks after the drug is discontinued (DC)
o Management
 Discontinuation of drug
 Metronidazole (1st line ) or oral Vancomycin (2nd line)
 Skin rash (10%) & SJS
 Inhibits neuromuscular transmission and potentiates skeletal
muscle relaxants (atracurium) like aminoglycoside antibiotics
 2-Chloramphenicol
 Bacteriostatic & activity against G +ve & G –ve bacteria (include
MRSA) and anaerobes
 Lipid soluble and cross BBB

 Therapeutic indications
 It is used to treat ocular infections caused by Staphylococcus aurous
 It is used to treat meningitis & typhoid fever caused by Salmonella typhi
o 3rd generation cephalosporin and quinolones are first line

 M.O.A
 Acts at 50S & inhibits the peptidyl transferase leading to inhibition of
peptide bound formation between a.a residues of growing peptide
 2-Chloramphenicol
 Adverse reactions
 Bone marrow suppression (70% of cases are aplastic anemia)
 Loss of vision
 Gray baby syndrome occurs in newborn infants
o Vomiting, Hypotension, cyanosis, CVS collapse and death (40% of
patients within 2 days of symptoms)
o Due to accumulation of toxic metabolites of chloramphenicol
 Jarisch-Herxheimer reactions following the treatment of syphilis and
typhoid fever

 Used restricted for life-threatening situations in developed countries

 Patients who cannot take safer alternative antibiotic due to resistance
or allergies
 PROBLEM: It is still used regularly in developing countries (cheap)
 3-Streptogramins (Synercid®)
 A combination of quinupristin & dalfopristin; in a ratio 30:70

 The combination is bactericidal & very active against Gram +ve

cooci and atypical pneumonia

 BUT inactive against Gram –ve bacteria

 Therapeutic indications
 Used IV to treat VRSA as well as vancomycin-resistant
Enterococcus (VRE) infections
Streptogramins – quinupristin-dalfopristin (Synercid®)
 M.O.A
 Quinupristin
o Has similar mechanism as macrolides (binds at 50S)
o Inhibits the translocation of ribosome complex and polypeptide
elongation

 Dalfopristin
o Binds to 50S ribosme, resulting in a conformation change in
ribosome leading to….
 Inhibition of peptidyl transferase
 Enhancement the binding of quinupristin to the 50S subunit by
a factor of about 100

 Adverse effects
 Arthralgia and myalgia
Streptogramins – quinupristin-dalfopristin (Synercid®)