Lincosamides
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Lincosamides are a class of
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
, which include
lincomycin Lincomycin is a lincosamide antibiotic that comes from the actinomycete ''Streptomyces lincolnensis''. A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-hydroxy group with a chlorine atom with ...
,
clindamycin Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (mi ...
, and
pirlimycin Pirlimycin, sold under the brand name Pirsue, is used in the treatment of mastitis in cattle. It is used as the salt pirlimycin hydrochloride and it belongs to the lincosamide class of antimicrobials. __TOC__ Activity Pirlimycin is active aga ...
.


Structure

Lincosamides consist of a
pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...
ring linked to a
pyranose In organic chemistry, pyranose is a collective term for saccharides that have a chemical structure that includes a six-membered ring consisting of five carbon atoms and one oxygen atom (a heterocycle). There may be other carbons external to the ...
moiety (methylthio-lincosamide) via an amide bond. Hydrolysis of lincosamides, specifically lincomycin, splits the molecule into its building blocks of the sugar and proline moieties. Both of these derivatives can conversely be recombined into the drug itself or a derivative.


Synthesis

Biosynthesis of lincosamides occurs through a biphasic pathway, in which propylproline and methylthiolincosamide are independently synthesized immediately before condensation of the two precursor molecules. Condensation of the propylproline carboxyl group with the methylthiolincosamide amine group via an amide bond forms ''N''-demethyllincomycin. ''N''-Demethyllincomycin is subsequently
methylated Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...
via ''S''-adenosyl methionine to produce lincomycin A. Lincomycin is naturally produced by bacteria species, namely '' Streptomyces lincolnensis'', '' S. roseolus'', and '' S. caelestis''.
Clindamycin Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (mi ...
is derived via (7''S'')-
chloro Chlorine is a chemical element; it has symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine is a ...
- substitution of the (7''R'')-
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group of lincomycin. Lincomycin is primarily isolated from fermentations of ''Streptomyces lincolnensis,'' while clindamycin is prepared semi-synthetically. While several hundred synthetic and semi-synthetic derivatives of lincosamides have been prepared, only lincomycin A and clindamycin are used in clinical practice due to issues with toxicity and low biological activity in other lincosamide antibiotics.


Mechanism of action

Lincosamides prevent bacterial replication in a
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, disinfec ...
mechanism by interfering with the synthesis of proteins. In a mechanism similar to
macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
s and streptogramin B, lincosamides bind close to the peptidyl transferase center on the 23S portion of the
50S 50 S is the larger subunit of the 70S ribosome of prokaryotes, i.e. bacteria and archaea. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the 5S ribosom ...
subunit of bacterial ribosomes. Under the influence of high resolution X-ray, structures of clindamycin and ribosomal subunits from bacterium have previously revealed exclusive binding to the 23S segment of the peptidyl transferase cavity. Binding is mediated by the mycarose sugar moiety which has partially overlapping substrates with
peptidyl transferase The peptidyl transferase center (, PTC) is an Aminoacyltransferases, aminoacyltransferase ribozyme (RNA enzyme) located in the large subunit of the ribosome. It forms peptide bonds between adjacent amino acids during the Translation (genetics), ...
. By extending to the peptidyl transferase center, lincosamides cause the premature dissociation of peptidyl-tRNA's containing two, three or four amino acid residues. In this case, peptides will grow to a certain point until
steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...
inhibits peptidyl transferase activity.The Mechanism of Action of Macrolides, Lincosamides and Streptogramin B Reveals the Nascent Peptide Exit Path in the Ribosome
Martin Lovmar and Måns Ehrenberg
Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) due to structural differences between prokaryotic and eukaryotic ribosomes. Lincosamides are used against
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. The Gram stain ...
since they are unable to pass through the porins of
Gram-negative bacteria Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelo ...
.


Resistance


Ribosomal methylation

Soon after the emergence of clinical lincosamide use in 1953, strains of resistant
staphylococci ''Staphylococcus'', from Ancient Greek σταφυλή (''staphulḗ''), meaning "bunch of grapes", and (''kókkos''), meaning "kernel" or " Kermes", is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillale ...
were isolated in several countries including
France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...
,
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
and the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
. Resistant strains were characterized by expression of
methyltransferase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ro ...
s which dimethylate residues within the 23S subunit of ribosomal RNA, preventing binding of
macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
s, lincosamides and streptogramins B. The gene family responsible for encoding of these methyltransferases is referred to as the "''erm''" family, or erythromycin ribosome methylase family of genes. Nearly 40 ''erm'' genes have been reported to date, which are transferred primarily through
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 and ...
s and transposons.


Target mutation

Several strains of bacteria which are highly resistant to macrolide treatment have been isolated and found to possess mutations at the transferase binding pocket in the 23S ribosomal subunit. Macrolide-resistant ''
Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, hemolysis (microbiology), alpha-hemolytic member of the genus ''Streptococcus''. ''S. pneumoniae'' cells are usually found in pairs (diplococci) and do not f ...
''isolated from hospital patients in Eastern Europe and North America were found to contain mutations in either 23S or other ribosomal protein genes.


Antibiotic efflux

Gram-negative bacteria harbor genes encoding for molecular pumps which can contribute to resistance of hydrophobic compounds like macrolides and lincosamides. Out of the many families of multidrug resistance pumps, lincosamides are most commonly shunted through pumps belonging to the resistance-nodulation-cell division superfamily. Staphylococci express efflux pumps with specificity for 14 and 15 member ring macrolides and streptogramin B, but not lincosamide molecules.


Drug modification

Clinical isolates of ''S. aureus'' harboring genes which encode for lincosamide nucleotransferases have been reported. Genes lnuA and lnuB confer resistance to lincomycin, but not clindamycin. These genes, however, limit the bacteriostatic activity of clindamycin. This type of resistance is rare in ''S. aureus'', but has been reported to be more prevalent in other bacteria strains.


Pharmacokinetics

Approximately 90% of orally administered lincosamides are absorbed, with slight variance depending on which drug is given. Plasma concentrations via this route peak within 2–4 hours. Intramuscular administration of lincosamides results in strong absorption, with peak plasma levels being reached in 1–2 hours. Around 90% of clindamycin is bound to plasma proteins, and is generally more stable and rapidly absorbed than lincomycin. Lincosamides have a broad distribution in several tissues, excluding
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. When administered intramuscularly to rats, lincomycin was found to accumulate in highest concentrations in the kidneys when compared to other tissues, while clindamycin was found in highest concentrations within the lungs. Clindamycin accumulates in macrophages and other white blood cells, which can result in concentrations 50 times higher than plasma levels.


Clinical use

Lincosamides are often used clinically as an alternative antibiotic for patients who are allergic to
penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
. Of the lincosamides,
clindamycin Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (mi ...
is most commonly used within the clinic due to its higher bioavailability, higher oral absorption and efficacy within the target organism spectrum. Lincosamides are generally the first-choice use antibiotic class in veterinary microbiology, most commonly used to combat skin infections. Potential clinical uses for lincosamide antibiotics in humans are numerous. They are efficacious in the treatment of dental infections, abdominal infections, abscesses, pelvic inflammatory disease and anaerobic infections. Clindamycin alone has been shown to be efficacious in the treatment of
acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...
,
toxic shock syndrome Toxic shock syndrome (TSS) is a condition caused by Exotoxin, bacterial toxins. Symptoms may include fever, rash, skin peeling, and low blood pressure. There may also be symptoms related to the specific underlying infection such as mastitis, ...
and
malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
, and to decrease the risk of premature births in women with
bacterial vaginosis Bacterial vaginosis (BV) is an infection of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urina ...
. Lincosamide antibiotics may also be useful in the treatment of methicillin-resistant ''S. aureus''.


Toxicity and interactions

While there have been no reports of severe organ toxicity from lincosamide treatment, gastrointestinal disturbances have been associated with their administration. Pseudomembranous enterocolitis resulting from clindamycin-induced disruption of gastrointestinal flora can be a lethal adverse event observed in several species when used in the veterinary clinic, particularly in horses. At extremely high doses of clindamycin, skeletal muscle paralysis has been demonstrated in several species. Lincosamides can interact with anesthetic agents to produce neuromuscular effects. Other adverse reactions include diarrhea, nausea, vomiting, abdominal pain and rash. Topical administration of clindamycin may induce contact dermatitis, dryness, burning, itching, scaliness and peeling of the skin.


Lincosamide brand name formulations

* Clindamycin - Cleocin, Cleocin Pediatric, ClindaMax Vaginal, Dalacin * Lincomycin - Lincocin * Pirlimycin


History

The first lincosamide compound discovered was lincomycin, isolated from '' Streptomyces lincolnensis'' in a soil sample from Lincoln, Nebraska (hence the bacterial name).


Further reading

* Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen ''J. Infectious diseases''. Mosby, London, 1999, pp7/1.1-7/1.14


References

{{Macrolides, lincosamides and streptogramins