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 bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
, 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, and
pirlimycin
Pirlimycin hydrochloride belongs to the lincosamide class of antimicrobials. Under the trade name Pirsue, it is used in the treatment of mastitis in cattle.
Activity
Pirlimycin is active against Gram-positive bacteria, specifically '' Staphyloco ...
.
Structure
Lincosamides consist of a
pyrrolidine ring linked to a
pyranose 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
In the chemical sciences, methylation denotes 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 ...
via
''S''-adenosyl methionine to produce lincomycin A.
Lincomycin is naturally produced by bacteria species, namely ''
Streptomyces lincolnensis
''Streptomyces lincolnensis'' is a bacterium species in the type genus '' Streptomyces''.
''S. lincolnensis'' produces the antibacterial lincomycin. It also produces valienol
Valienol (streptol) is a C-7 cyclitol similar in structure to val ...
'', ''
S. roseolus
''Streptomyces roseolus'' is a bacterium species from the genus of ''Streptomyces'' which has been isolated from soil in Russia. ''Streptomyces roseolus'' produces chitosanase and isoflavones
.
See also
*
*
*
See also
* List of Streptom ...
'', and ''
S. caelestis
''Streptomyces caelestis'' is a bacterium species from the genus of '' Streptomyces'' which has been isolated from soil in Utah in the United States.Deutsche Sammlung von Mikroorganismen und Zellkulturenbr>/ref> ''Streptomyces caelestis'' produc ...
''.
Clindamycin is derived via (7''S'')-
chloro-
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, disinfect ...
mechanism by
interfering with the synthesis of proteins.
In a mechanism similar to
macrolide
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 rings are usually 14-, 15-, or 16-membered. Ma ...
s and
streptogramin B, lincosamides bind close to the peptidyl transferase center on the
23S portion of the
50S 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 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 subs ...
. 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 a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
inhibits peptidyl transferase activity.
[The Mechanism of Action of Macrolides, Lincosamides and Streptogramin B Reveals the Nascent Peptide Exit Path in the Ribosome](_blank)
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.
Gram-positive bact ...
since they are unable to pass through the
porins
Porins are beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse. Unlike other membrane transport proteins, porins are large enough to allow passive diffusion, i.e., they act as channels tha ...
of
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 ...
.
Resistance
Ribosomal methylation
Soon after the emergence of clinical lincosamide use in 1953, strains of resistant
staphylococci
''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical ( cocci), and form in grape-like clusters. ''Staphylococcus'' species are facultati ...
were isolated in several countries including
France
France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
,
Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
and the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
. 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 Ross ...
s which dimethylate residues within the 23S subunit of ribosomal RNA, preventing binding of
macrolide
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 rings are usually 14-, 15-, or 16-membered. Ma ...
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; how ...
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, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They ar ...
''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
Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND 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 body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
. 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 β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
. Of the lincosamides,
clindamycin 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 skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
toxic shock syndrome
Toxic shock syndrome (TSS) is a condition caused by 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, osteomyeli ...
and
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
, and to decrease the risk of premature births in women with
bacterial vaginosis
Bacterial vaginosis (BV) is a disease 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 urination ...
. 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
''Streptomyces lincolnensis'' is a bacterium species in the type genus '' Streptomyces''.
''S. lincolnensis'' produces the antibacterial lincomycin. It also produces valienol
Valienol (streptol) is a C-7 cyclitol similar in structure to val ...
'' 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