ANTIRIBOSOMAL ANTIBIOTICS

LEARNING OBJECTIVES
• To recognize the different antibiotics that inhibit ribosomal
activity, their mechanism of action, spectrum, side effects and
resistance

Since we only want to inhibit the growth of pathogenic bacterial

cells during an infection and not our own cells, we are fortunate
that bacteria actually have a different type of ribosome than we do.
We can use this difference by specifically inhibiting the ribosomes
of bacteria, while sparing the function of our own ribosomes.

CHLORAMPHENICOL:

This drug has an amazing spectrum of activity. It is one of the few

drugs (like Imipenem) that kill most clinically important
bacteria. Gram positive, gram negative, and even anaerobic
bacteria are susceptible.

Mechanism of action:
It binds to 50s ribosomal subunit preventing formation of peptide
bonds. Hence, preventing protein synthesis. Site of action of
chloramphenicol is overlapping with site of action of Macrolides
and Lincosamides, so it is antagonized by these drugs.

Clinical use:
1- It is used to treat bacterial meningitis, when the organism is not
yet known and the patient has severe allergies to the penicillins,
including the cephalosporins. This is because is has a wide
spectrum of activity and excellent penetration into CSF.
2- Rocky Mountain spotted fever in young children and pregnant
females.
N.B. In developing countries, this drug is widely used because of
its cheap price and wide spectrum of activity.

Resistance:
1- Production of inactivating enzymes by the bacteria. This
mechanism is plasmid mediated.
2- Alteration of the target.
3- Decreased permeability and production of efflux pump.

Side effects:
1- This drug is famous for 2 types of bone marrow depression. The
first is reversible and often only causes an anemia. The second
type wipes out the bone marrow and is usually fatal. This is
called aplastic anemia.
2- Gray baby syndrome: Neonates are unable to fully conjugate
chloramphenicol in the liver resulting in very high blood levels,
resulting in cyanosis, which appears as a gray color.
3- Optic neuritis.

CLINDAMYCIN
It has the same mechanism of action and resistance of macrolides
(see later).

Clinical use:
It is not useful against gram negative bacteria. It is used to treat
many gram positive and anaerobic infections. Surgeons use
clinadamycin along with an aminoglycoside for penetrating wound
infections of the abdomen.
It is also used for infections of the female genital tract, such as
septic abortions, as there are a lot of anaerobes here.

Side effects:
It can cause Pseudomembranous colitis. It destroys the natural
flora of the GI tract, allowing Clostridium difficile to grow and
secrete exotoxin, causing pseudomembranous colitis.

MACROLIDES
They may be old generation e.g. Erythromycin, or new generation
e.g. Azithromycin.
Mechanism of action:
They bind to part of the 50s ribosomal subunit preventing protein
synthesis.

Resistance:
The bacteria produce enzymes that decompose the drug.

Erythromycin:

Clinical use:
Gram positive organisms absorb erythromycin 100 times better
than gram negative organisms. It is inactive against most gram
negatives.
It is the drug of choice for community-acquired pneumonia that
does not require hospitalization. It covers Streptococcus
pneumoniae, Mycoplasma pneumoniae, and Chlamydia
trachomatis.

Side effects:
It is one of the safest antibiotics.
1- Abdominal pain (GI irritation)
2- Rare cholestatic hepatitis
3- Rash
4- Auditory dysfunction

Azithromycin:
It can be used for the treatment of (Chlamydial) non-gonococcal
uretheritis.

TETRACYCLINES/DOXYCYCLINES

Tetracycline chelates with milk and milk products, aluminum

hydroxide, Ca++, and Mg++. When it is chelated, it will pass through
the intestine without being absorbed. Doxycycline is a tetracycline
that chelates cations poorly and is thus better absorbed with food.

Mechanism of action:
They bind to the 30s ribosomal subunit.

Clinical use:
1- venereal diseases caused by Chlamydia trachomatis
2- pneumonia caused by Mycoplasma pneumonia (as an alternative
to erythromycin)
3- Animal and tick-borne diseases caused by Brucella and
Rickettsia.
4- Acne

Resistance:
1- reduction of intracellular drug concentration by decrease of
permeation and efflux pump
2- modification of the target (30s subunit)
3- production of enzymes that decompose the antibiotic

Side effects:
1- GI irritation
2- Phototoxic dermatitis (skin inflammation on exposure to
sunlight)
3- Renal and hepatic toxicity
4- Discolored teeth and depressed bone growth.

AMINOGLYCOSIDES

They must diffuse across the cell wall to enter the bacterial cell, so
they are often used with penicillin, which breaks down this wall to
facilitate diffusion.

Mechanism of action:
1- They bind irreversibly to 30s ribosomal subunit
2- Cause leakage of the cytoplasmic membrane
3- Cause misreading of mRNA

Clinical use:
They kill aerobic gram negative enteric organisms. They are
among the handful of drugs that kill Pseudomonas aeruginosa.

Most of the aminoglycosides end with –mycin.

1- Streptomycin is the oldest one in the family. Many bacteria
have developed resistance to it.
2- Gentamicin: is the most commonly used of all the
aminoglycosides. It is combined with penicillins to treat in-
hospital infections.
3- Tobramycin is good against Pseudomonas aeruginosa
4- Amikacin: does not end with mycin. It has the broadest
spectrum and is good for hospital acquired (nosocomial)
infections that have developed resistance to other drugs.
5- Neomycin: has very broad coverage but is too toxic, so it can
only be used topically for skin infections

Useful combinations with aminoglycosides include:

Rifampicin+streptomycin+isoniazide
for treatment of TB
Streptomycin+penicillin
subacute bacterial endocarditis (SABE)
Streptomycin+tetracycline
plague

Resistance:
1- Production of inactivating enzymes
2- Mutation of the target (30s subunit)
3- Reduction of permeability

Side effects:
1- Nephrotoxicity
2- Ototoxicity
3- Neuromuscular blockade
4- Contact dermatitis

SPECTINOMYCIN:
This drug has a name that sounds like an aminoglycoside, but it is
different structurally and biologically. Its mechanism is similar in
that it acts on the 30s ribosome to inhibit protein synthesis. It is
given as an IM injection.

Clinical use:
It is used to treat gonorrhea as an alternative to penicillin and
tetracycline, since many strains are resistant to these drugs.