Macrolide
Encyclopedia
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 sugar
s, 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 product
s.
Not US FDA-approved:
Ketolides include:
, pimecrolimus
, and sirolimus
, which are used as immunosuppressant
s or immunomodulators, are also macrolides. They have similar activity to cyclosporin.
s.
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.
s. 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
. Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.
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.
, Asian-prevalent lung disease diffuse panbronchiolitis
(DPB).
The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response), with the added benefit of low-dose
requirements.
With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte
proliferation but also lymphocyte
activity and obstructive secretion
s in airways. The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB. 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.
bacterial ribosomal RNA. This acquired resistance can be either plasmid
-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides
, and streptogramins (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.
Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes
) in penicillin-sensitive patients, however macrolide-resistant strains of GAS are not uncommon. Cephalosporin
is another option for these patients.
. 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)
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
(typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic
Macrocycle
A macrocycle is, as defined by IUPAC, "a cyclic macromolecule or a macromolecular cyclic portion of a molecule." In the chemical literature, organic chemists may consider any molecule containing a ring of nine or more atoms to be a macrocycle...
lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
ring to which one or more deoxy sugar
Deoxy sugar
Deoxy sugars are sugars that have had a hydroxyl group replaced with a hydrogen atom.Examples include:* Deoxyribose * Fucose* Rhamnose-External links:*...
s, usually cladinose
Cladinose
Cladinose is a hexose deoxy sugar that in several antibiotics is attached to the macrolide ring.In ketolides, a relatively new class of antibiotics, the cladinose is replaced with a keto group.-External links:* *...
and desosamine
Desosamine
Desosamine is a 3--3,4,6-trideoxyhexose found in certain macrolide antibiotics such as the commonly prescribed erythromycin.-Biosynthesis:Six enzymes are required for its biosynthesis from TDP-glucose in Streptomyces venezuelae....
, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...
class of natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
s.
Antibiotic macrolides
US FDA-approved :- AzithromycinAzithromycinAzithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...
- unique, does not inhibit CYP3A4CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... - ClarithromycinClarithromycinClarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
- DirithromycinDirithromycinDirithromycin is a macrolide glycopeptide antibiotic.Dirithromycin is a more lipid-soluble prodrug derivative of 9S-erythromycyclamine prepared by condensation of the latter with 2-acetaldehyde...
- ErythromycinErythromycinErythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
- RoxithromycinRoxithromycinRoxithromycin is a semi-synthetic macrolide antibiotic. It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side chain is attached to the lactone ring...
- TelithromycinTelithromycinTelithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek....
Not US FDA-approved:
- Carbomycin A
- JosamycinJosamycinJosamycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces narbonensis var. josamyceticus var. novaCurrently sold in various countries.Brand examples are:...
- KitasamycinKitasamycinKitasamycin is a macrolide antibiotic. It is produced by streptomyces kitasatoensis. The drug has antimicrobial activity against a wide spectrum of pathogens....
- MidecamycinMidecamycinMidecamycin is a macrolide antibiotic. Synthesized from Streptomyces mycarofaciens.-Physical Properties:Melting point vary depending on the compound type. It may also vary depending on the source consulted...
/midecamycin acetate - OleandomycinOleandomycinOleandomycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces antibioticus. It is weaker than erythromycin.It used to be sold under the brand name Sigmamycine, combined with Tetracycline, and made by the company Rosa-Phytopharma in France....
- SolithromycinSolithromycinSolithromycin is a novel ketolide antibiotic undergoing clinical development for the treatment of community acquired pneumonia and other infections...
- SpiramycinSpiramycinSpiramycin is a macrolide antibiotic. It is used to treat toxoplasmosis. Although used in Europe, Canada and Mexico, spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of...
- approved in Europe and other countries - TroleandomycinTroleandomycinTroleandomycin is a macrolide antibiotic. It is currently sold in Italy and Turkey.Side effects: It is a CYP3A4 inhibitor....
- used in Italy and Turkey - TylosinTylosinTylosin is a macrolide-class antibiotic used in veterinary medicine. It has a broad spectrum of activity against gram positive organisms and a limited range of gram negative organisms...
/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:
- TelithromycinTelithromycinTelithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek....
- CethromycinCethromycinCethromycin is a ketolide antibiotic undergoing research for the treatment of community acquired pneumonia and for the prevention of post-exposure inhalational anthrax, and was given an "orphan drug" status for this indication. Originally discovered and developed by Abbott, it was acquired by...
- SolithromycinSolithromycinSolithromycin is a novel ketolide antibiotic undergoing clinical development for the treatment of community acquired pneumonia and other infections...
- the first fluoroketolide - SpiramycinSpiramycinSpiramycin is a macrolide antibiotic. It is used to treat toxoplasmosis. Although used in Europe, Canada and Mexico, spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of...
- used for treating toxoplasmosisToxoplasmosisToxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself... - AnsamycinAnsamycinAnsamycins is a family of secondary metabolites that show antimicrobial activity against many gram-positive and some gram-negative bacteria and includes various compounds, among which: streptovaricins and rifamycins...
- OleandomycinOleandomycinOleandomycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces antibioticus. It is weaker than erythromycin.It used to be sold under the brand name Sigmamycine, combined with Tetracycline, and made by the company Rosa-Phytopharma in France....
- Carbomycin
- Tylocine
Non-antibiotic macrolides
The drugs tacrolimusTacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
, pimecrolimus
Pimecrolimus
Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis . It is currently available as a topical cream, once marketed by Novartis under the trade name Elidel.-Pharmacology:Pimecrolimus is an ascomycin macrolactam derivative...
, and sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
, which are used as immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
s 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 mycolactoneMycolactone
Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic mycobacteria that have been assigned a variety of species names including, M. ulcerans, M. liflandii , M. pseudoshottsii, and some strains of M. marinum...
s.
Uses
Antibiotic macrolides are used to treat infections caused by Gram-positiveGram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria, Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
, and Haemophilus influenzae
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
infections such as respiratory tract and soft-tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, 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
Legionella pneumophila
Legionella pneumophila is a thin, ærobic, pleomorphic, flagellated, non-spore forming, Gram-negative bacterium of the genus Legionella. L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease.-Characterization:L...
, mycoplasma
Mycoplasma
Mycoplasma refers to a genus of bacteria that lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans,...
, mycobacteria, some rickettsia
Rickettsia
Rickettsia is a genus of non-motile, Gram-negative, non-sporeforming, highly pleomorphic bacteria that can present as cocci , rods or thread-like . Being obligate intracellular parasites, the Rickettsia survival depends on entry, growth, and replication within the cytoplasm of eukaryotic host cells...
, and chlamydia
Chlamydia (bacterium)
Chlamydia is a genus of bacteria that are obligate intracellular parasites. Chlamydia infections are the most common bacterial sexually transmitted infections in humans and are the leading cause of infectious blindness worldwide....
.
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.
Antibacterial
Macrolides are protein synthesis inhibitorProtein synthesis inhibitor
A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins....
s. The mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
of macrolides is inhibition
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of bacterial protein biosynthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
, and they are thought to do this by preventing peptidyltransferase from adding the peptidyl attached to tRNA
Transfer RNA
Transfer RNA is an adaptor molecule composed of RNA, typically 73 to 93 nucleotides in length, that is used in biology to bridge the three-letter genetic code in messenger RNA with the twenty-letter code of amino acids in proteins. The role of tRNA as an adaptor is best understood by...
to the next amino acid (similarly to chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
) as well as inhibiting ribosomal translocation
Ribosomal translocation
Ribosomal translocation is a step in both:*Eukaryotic elongation and*Prokaryotic elongation, during translation of messenger RNA into proteins...
. Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.
Macrolide antibiotics do so by binding reversibly to the P site on the subunit 50S
50S
50S is the larger subunit of the 70S ribosome of prokaryotes. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the subunits 5S and 23S.-Structure:...
of the bacterial ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
. 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.
Diffuse panbronchiolitis
The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for the idiopathicIdiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
, Asian-prevalent lung disease diffuse panbronchiolitis
Diffuse panbronchiolitis
Diffuse panbronchiolitis is an inflammatory lung disease of unknown cause. It is a severe, progressive form of bronchiolitis, which is inflammation of the bronchioles, small air passages in the lungs...
(DPB).
The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response), with the added benefit of low-dose
Dosing
Dosing generally applies to feeding chemicals or medicines in small quantities into a process fluid or to a living being at intervals or to atmosphere at intervals to give sufficient time for the chemical or medicine to react or show the results....
requirements.
With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
proliferation but also lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
activity and obstructive secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
s in airways. The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB. 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
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
, macrolide therapy still produces substantial anti-inflammatory results.
Resistance
The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S23S ribosomal RNA
The 23S rRNA is a 2904 nt long component of the large prokaryotic subunit The ribosomal peptidyl transferase activity resides in this rRNA...
bacterial ribosomal RNA. This acquired resistance can be either plasmid
Plasmid
In microbiology and genetics, a plasmid is a DNA molecule that is separate from, and can replicate independently of, the chromosomal DNA. They are double-stranded and, in many cases, circular...
-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides
Lincosamides
Lincosamides are a class of antibiotics.-Mechanism of action:Lincosamides kill bacteria by interfering with the synthesis of proteins. They bind to the 23s portion of the 50S subunit of bacterial ribosomes and cause premature dissociation of the peptidyl-tRNA from the ribosome...
, and streptogramins (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.
Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
) in penicillin-sensitive patients, however macrolide-resistant strains of GAS are not uncommon. Cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
is another option for these patients.
Side-effects
A 2008 British Medical Journal article highlights that the combination of macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathyMyopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
. This is because macrolides are potent inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of the cytochrome P450 system, particularly of CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. 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
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of 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)
External links
- Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships", André Bryskier MD; beginning at pp143