The
macrolides are a group of
drugs (typically
antibiotics) whose activity stems from the presence of a
macrolide ring, 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. Macrolides belong to the
polyketide class of
natural products.
. The macrolide ring is the lactone (cyclic ester) at upper-left.]]
Members
Antibiotic macrolides
US FDA-approved :
Azithromycin - unique, does not inhibit CYP3A4
Clarithromycin
Dirithromycin
Erythromycin
Roxithromycin
Telithromycin
Not US FDA-approved:
Carbomycin A
Josamycin
Kitasamycin
Midecamycin/midecamycin acetate
Oleandomycin
Solithromycin
Spiramycin - approved in Europe and other countries
Troleandomycin - used in Italy and Turkey
Tylosin/tylocine - used in animals
Ketolides
Ketolides are a new class of antibiotics that are structurally related to the macrolides. They are used to treat respiratory tract infections caused by macrolide-resistant bacteria. Ketolides are especially effective, as they have two ribosomal binding sites; the newer fluoroketolides have three ribosomal interaction sites.
Ketolides include:
Telithromycin
Cethromycin
Solithromycin - the first fluoroketolide
Spiramycin - used for treating toxoplasmosis
Ansamycin
Oleandomycin
Carbomycin
Tylocine
Non-antibiotic macrolides
The drugs
tacrolimus,
pimecrolimus, and
sirolimus, which are used as
immunosuppressants or immunomodulators, are also macrolides. They have similar activity to
cyclosporin.
Toxic macrolides
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the
mycolactones.
Uses
Antibiotic macrolides are used to treat infections caused by
Gram-positive bacteria,
Streptococcus pneumoniae, and
Haemophilus influenzae infections such as respiratory tract and soft-tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of
penicillin, and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic
streptococci,
pneumococci,
staphylococci, and
enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against
Legionella pneumophila,
mycoplasma,
mycobacteria, some
rickettsia, and
chlamydia.
Macrolides are not to be used on non-ruminant herbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance. It can be used in horses less than one year old, but care must be taken that other horses (such as a foal's mother) do not come in contact with the macrolide treatment.
Mechanism of action
Antibacterial
Macrolides are
protein synthesis inhibitors. The
mechanism of action of macrolides is
inhibition of bacterial
protein biosynthesis, and they are thought to do this by preventing
peptidyltransferase from adding the peptidyl attached to
tRNA to the next amino acid (similarly to
chloramphenicol) as well as inhibiting
ribosomal translocation.
Macrolide antibiotics do so by binding reversibly to the P site on the subunit 50S of the bacterial ribosome. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are, therefore, transported into the site of infection.
Immunomodulation
Diffuse panbronchiolitis
The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for the
idiopathic, Asian-prevalent lung disease
diffuse panbronchiolitis (DPB).
The successful results of macrolides in DPB stems from controlling symptoms through
immunomodulation (adjusting the immune response), This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of the macrolide-resistant bacterium
Pseudomonas aeruginosa, macrolide therapy still produces substantial anti-inflammatory results. This is because macrolides are potent
inhibitors of the
cytochrome P450 system, particularly of
CYP3A4. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of
QT prolongation, which can lead to
torsade de pointes. Macrolides exhibit
enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the
duodenum in bile from the liver. This can lead to a build-up of the product in the system, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis. (ref at PMID: 1263054 and PMID: 10609814)
Bibliography
References
External links
Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships", André Bryskier MD; beginning at pp143
