The Macrolides are a class of
natural product
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...
s that consist of a large
macrocyclic
Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry.
...
lactone ring to which one or more
deoxy sugars, usually
cladinose and
desosamine
Desosamine is a 3-(dimethylamino)-3,4,6-trideoxyhexose found in certain macrolide antibiotics (contain a high level of microbial resistance) such as the commonly prescribed erythromycin, azithromycin, clarithroymcin, methymycin, narbomycin, ol ...
, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the
polyketide
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
class of natural products. Some macrolides have
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
or
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...
activity and are used as
pharmaceutical drug
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
s.
Rapamycin is also a macrolide and was originally developed as an antifungal, but is now used as an
immunosuppressant drug
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be classified into ...
and is being investigated as a potential
longevity therapeutic.
Macrolides are bacteriostatic in that they suppress or inhibit bacterial growth rather than killing bacteria completely.
Definition
In general, any macrocyclic lactone having greater than 8-membered rings are candidates for this class. The macrocycle may contain
amino
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
nitrogen,
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
nitrogen (but should be differentiated from
cyclopeptides), an
oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a we ...
ring, or a
thiazole
Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular fo ...
ring.
Benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms ...
rings are excluded, in order to differentiate from
tannins. Also
lactams
A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words '' lactone'' + ''amide''.
Nomenclature
Greek prefixes in alphabetical order indicate ring size:
* α-Lactam (3-atom rings)
* β-Lac ...
instead of lactones (as in the
ansamycin family) are excluded. Included are not only 12-16 membered macrocycles but also larger rings as in
tacrolimus.
History
The first macrolide discovered was
erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used durin ...
, which was first used in 1952. Erythromycin was widely used as a substitute to
penicillin
Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
in cases where patients were allergic to penicillin or had penicillin-resistant illnesses. Later macrolides developed, including
azithromycin and
clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...
, stemmed from chemically modifying erythromycin; these compounds were designed to be more easily absorbed and have fewer side-effects (erythromycin caused gastrointestinal side-effects in a significant proportion of users).
Uses
Antibiotic macrolides are used to treat infections caused by
Gram-positive bacteria
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bac ...
(e.g., ''
Streptococcus pneumoniae
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They ar ...
'') and limited
Gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
(e.g., ''
Bordetella pertussis
''Bordetella pertussis'' is a Gram-negative, aerobic, pathogenic, encapsulated coccobacillus of the genus ''Bordetella'', and the causative agent of pertussis or whooping cough. Like '' B. bronchiseptica'', ''B. pertussis'' is motile and exp ...
'', ''
Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bact ...
''), and some respiratory tract and soft-tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of
penicillin
Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
, and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic
streptococci
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occu ...
,
pneumococci
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
,
staphylococci, and
enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against ''
Legionella pneumophila
''Legionella pneumophila'' is a thin, aerobic, 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 ...
'',
mycoplasma
''Mycoplasma'' is a genus of bacteria that, like the other members of the class '' Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan ( murein) is absent. This characteristic makes them naturally resistant to antibioti ...
,
mycobacteria
''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...
, some
rickettsia
''Rickettsia'' is a genus of nonmotile, gram-negative, nonspore-forming, highly pleomorphic bacteria that may occur in the forms of cocci (0.1 μm in diameter), bacilli (1–4 μm long), or threads (up to about 10 μm long). The term "ricke ...
, and
chlamydia
Chlamydia, or more specifically a chlamydia infection, is a sexually transmitted infection caused by the bacterium '' Chlamydia trachomatis''. Most people who are infected have no symptoms. When symptoms do appear they may occur only several we ...
.
Macrolides are ''not'' to be used on non
ruminant
Ruminants (suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. The ...
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 mare) do not come in contact with the macrolide treatment.
Macrolides can be administered in a variety of ways, including tablets, capsules, suspensions, injections and topically.
Mechanism of action
Antibacterial
Macrolides are
protein synthesis inhibitors. The
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
of macrolides is
inhibition of bacterial
protein biosynthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
, and they are thought to do this by preventing
peptidyltransferase
The peptidyl transferase is an aminoacyltransferase () as well as the primary enzymatic function of the ribosome, which forms peptide bonds between adjacent amino acids using tRNAs during the translation process of protein biosynthesis. The subst ...
from adding the growing peptide attached to
tRNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
to the next amino acid
[Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents](_blank)
Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009 (similarly to
chloramphenicol
Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, chole ...
) as well as inhibiting
bacterial ribosomal translation.
[ Another potential mechanism is premature dissociation of the ]peptidyl-tRNA Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.
Initiation
Initiation of translation in bacteria involves the assembly of the components of the translation system, which are: the two ribosomal ...
from the ribosome.
Macrolide antibiotics do so by binding reversibly to the P site on the 50S subunit of the bacterial ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to fo ...
. This action is considered to be bacteriostatic
A bacteriostatic agent or bacteriostat, abbreviated Bstatic, is a biological or chemical agent that stops bacteria from reproducing, while not necessarily killing them otherwise. Depending on their application, bacteriostatic antibiotics, disinfect ...
. Macrolides are actively concentrated within leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...
, and thus are 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
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
, Asian-prevalent lung disease diffuse panbronchiolitis
Diffuse panbronchiolitis (DPB) is an inflammatory lung disease of unknown cause. It is a severe, progressive form of bronchiolitis, an inflammatory condition of the bronchioles (small air passages in the lungs). The term ''diffuse'' signifies th ...
(DPB). The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation Immunomodulation is modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and thus the word can refer to the following:
* Homeostasis in the immune system, whereby the system self-regulates to adjust immun ...
(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
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
proliferation but also lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...
activity and obstructive secretion 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...
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'' is a common encapsulated, gram-negative, aerobic– facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. a ...
'', macrolide therapy still produces substantial anti-inflammatory results.[
]
Examples
Antibiotic macrolides
US FDA-approved :
* Azithromycin - unique; does not extensively inhibit CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...
*Clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...
*Erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used durin ...
Non-US FDA-approved:
* Carbomycin A
* Josamycin
*Kitasamycin
Kitasamycin (INN) is a macrolide antibiotic
The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone ...
* Midecamycin/midecamycin acetate
Midecamycin is a macrolide antibiotic that is synthesized from ''Streptomyces mycarofaciens''.
Physical Properties
Its melting point may vary depending on the compound type and the source consulted. For example, the Merck Index gives a melting ...
* Oleandomycin
* Solithromycin
* Spiramycin - approved in the EU, and in other countries
*Troleandomycin
Troleandomycin (TAO for short) is a macrolide antibiotic. It was sold in Italy (branded Triocetin) and Turkey (branded Tekmisin). It is no longer sold in Italy as of 2018.
The drug's mode of action is to bind to the ribosome, specifically in ...
- used in Italy and Turkey
* Tylosin/tylocine
Tylosin is a macrolide antibiotic and bacteriostatic feed additive used in veterinary medicine. It has a broad spectrum of activity against Gram-positive organisms and a limited range of Gram-negative organisms. It is found naturally as a fe ...
- used in animals
* Roxithromycin
Ketolides
Ketolides are a 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.
Ketolides include:
* Telithromycin - the first and only approved ketolide
* Cethromycin
* Solithromycin
Fluoroketolides
Fluoroketolides are a class of antibiotics that are structurally related to the ketolides. The fluoroketolides have three ribosomal interaction sites.
Fluoroketolides include:
* Solithromycin - the first and currently the only fluoroketolide (not yet approved)
Non-antibiotic macrolides
The drugs tacrolimus, pimecrolimus, and sirolimus, which are used as immunosuppressant
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be classified in ...
s or immunomodulators, are also macrolides. They have similar activity to ciclosporin.
Antifungal drugs
Polyene antimycotic Polyene antimycotics, sometimes referred to as polyene antibiotics, are a class of antimicrobial polyene compounds that target fungi. These polyene antimycotics are typically obtained from some species of ''Streptomyces'' bacteria. Previously, ...
s, such as amphotericin B
Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis ...
, nystatin etc., are a subgroup of macrolides. Cruentaren
Cruentarens are a group of macrolides secreted by the myxobacteria '' Byssovorax cruenta''. There are two isomers (cruentaren A and B) have been isolated. They each have a molecular formula of C33H51NO8 and molecular weight 589 g/mol. Cruentare ...
is another example of an antifungal macrolide.
Toxic macrolides
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the mycolactones.
Resistance
The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S
The 23S rRNA is a 2,904 nucleotide long (in '' E. coli'') component of the large subunit (50S) of the bacterial/archean ribosome and makes up the peptidyl transferase center (PTC). The 23S rRNA is divided into six secondary structural domains ...
bacterial ribosomal RNA. This acquired resistance can be either plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramin Streptogramins are a class of antibiotics.
Streptogramins are effective in the treatment of vancomycin-resistant ''Staphylococcus aureus'' (VRSA) and vancomycin-resistant ''Enterococcus'' (VRE), two of the most rapidly growing strains of multidru ...
s (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'' is a species of Gram-positive, aerotolerant bacteria in the genus '' Streptococcus''. These bacteria are extracellular, and made up of non-motile and non-sporing cocci (round cells) that tend to link in chains. They ...
'') in penicillin-sensitive patients, however macrolide-resistant strains of GAS are not uncommon. Cephalosporin
The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''.
Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
is another option for these patients.
Side-effects
A 2008 ''British Medical Journal
''The BMJ'' is a weekly peer-reviewed medical trade journal, published by the trade union the British Medical Association (BMA). ''The BMJ'' has editorial freedom from the BMA. It is one of the world's oldest general medical journals. Origi ...
'' article highlights that the combination of some macrolides and statins
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low ...
(used for lowering cholesterol) is not advisable and can lead to debilitating myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This me ...
. This is because some macrolides (clarithromycin and erythromycin, not azithromycin) are potent inhibitors of the cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
system, particularly of CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...
. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of QT prolongation
Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...
, which can lead to torsades de pointes
''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
. Macrolides exhibit enterohepatic recycling
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...
; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the 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 m ...
in bile from the liver. This can lead to a buildup of the product in the system, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis.
Some macrolides are also known to cause cholestasis, a condition where bile cannot flow from the liver to the duodenum. A new study found an association between erythromycin use during infancy and developing IHPS (Infantile hypertrophic pyloric stenosis) in infants. However, no significant association was found between macrolides use during pregnancy or breastfeeding.
A Cochrane review showed gastrointestinal symptoms to be the most frequent adverse event reported in literature.
Interactions
Macrolides should not be taken with colchicine
Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken b ...
as it may lead to colchicine toxicity. Symptoms of colchicine toxicity include gastrointestinal upset, fever, myalgia, pancytopenia, and organ failure.
References
Further reading
*
*
{{GlycopeptideAntiBio