lincosamides

Lincosamides consist of a pyrrolidine ring linked to a pyranose moiety (methylthio-lincosamide) via an amide bond.{{Cite journal|last1=Rezanka|first1=Tomas|last2=Spizek|first2=Jaroslav|last3=Sigler|first3=Karel|date=2007-04-01|title=Medicinal Use of Lincosamides and Microbial Resistance to Them|journal=Anti-Infective Agents in Medicinal Chemistry|language=en|volume=6|issue=2|pages=133–144|doi=10.2174/187152107780361670|issn=1871-5214}}{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/56842237#section=Top|title=Lincosamides|last=Pubchem|website=pubchem.ncbi.nlm.nih.gov|language=en|access-date=2018-09-19}} 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.{{cite journal |last=Le Goffic |first=Francois |title=Structure activity relationships in lincosamide and streptogramin antibiotics |journal=Journal of Antimicrobial Chemotherapy |date=1 January 1985 |volume=16 |issue=suppl A |pages=13–21 |doi=10.1093/jac/16.suppl_a.13 |pmid=3932299 |url=https://academic.oup.com/jac/article-abstract/16/suppl_A/13/779346}}

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 via S-adenosyl methionine to produce lincomycin A.{{Cite journal|url=https://www.researchgate.net/publication/233549124|title=Medicinal Use of Lincosamides and Microbial Resistance to Them|journal=Anti-Infective Agents in Medicinal Chemistry|volume=6|issue=2|pages=133–144|language=en|access-date=2018-10-07|doi=10.2174/187152107780361670|year=2007|last1=Rezanka|first1=Tomas|last2=Spizek|first2=Jaroslav|last3=Sigler|first3=Karel}}{{Cite web|url=http://ucsdchem257.pbworks.com/w/page/10600804/Lincomycin|title=ucsdchem257 / Lincomycin|website=ucsdchem257.pbworks.com|language=en|access-date=2018-11-10}}

Lincomycin is naturally produced by bacteria species, namely Streptomyces lincolnensis, S. roseolus, and S. caelestis.{{Cite journal|date=2017-06-01|title=Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications|journal=Biochemical Pharmacology|language=en|volume=133|pages=20–28|doi=10.1016/j.bcp.2016.12.001|pmid=27940264|issn=0006-2952|last1=Spížek|first1=Jaroslav|last2=Řezanka|first2=Tomáš|s2cid=21224168}} Clindamycin is derived via (7S)-chloro-substitution of the (7R)-hydroxyl group of lincomycin.{{Cite journal|last1=Birkenmeyer|first1=Robert D.|last2=Kagan|first2=Fred.|date=July 1970|title=Lincomycin. XI. Synthesis and structure of clindamycin, a potent antibacterial agent|journal=Journal of Medicinal Chemistry|language=en|volume=13|issue=4|pages=616–619|doi=10.1021/jm00298a007|pmid=4916317|issn=0022-2623}} Lincomycin is primarily isolated from fermentations of Streptomyces lincolnensis, while clindamycin is prepared semi-synthetically.{{Cite journal|last1=Spížek|first1=J.|last2=Řezanka|first2=T.|date=2004-02-05|title=Lincomycin, clindamycin and their applications|journal=Applied Microbiology and Biotechnology|language=en|volume=64|issue=4|pages=455–464|doi=10.1007/s00253-003-1545-7|pmid=14762701|s2cid=7870760|issn=0175-7598}} 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.

File:Lincomycin_A_Synthesis.png

Lincosamides prevent bacterial replication in a bacteriostatic mechanism by interfering with the synthesis of proteins.

In a mechanism similar to macrolides 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.{{Cite journal|last1=Schlünzen|first1=Frank|last2=Zarivach|first2=Raz|last3=Harms|first3=Jörg|last4=Bashan|first4=Anat|last5=Tocilj|first5=Ante|last6=Albrecht|first6=Renate|last7=Yonath|first7=Ada|last8=Franceschi|first8=François|date=October 2001|title=Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria|journal=Nature|language=En|volume=413|issue=6858|pages=814–821|doi=10.1038/35101544|pmid=11677599|issn=0028-0836|bibcode=2001Natur.413..814S|s2cid=205022511}} Binding is mediated by the mycarose sugar moiety which has partially overlapping substrates with peptidyl transferase. 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 inhibits peptidyl transferase activity.[https://web.archive.org/web/20090825062300/http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WK7-490R2TT-C&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=19d53b7156b390f5ed0a09eb156c18ea 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 since they are unable to pass through the porins of Gram-negative bacteria.

File:Clindamycin_mechanism.png

Soon after the emergence of clinical lincosamide use in 1953, strains of resistant staphylococci were isolated in several countries including France, Japan and the United States.{{Cite journal|last=Weisblum|first=B|date=March 1995|title=Erythromycin resistance by ribosome modification.|journal=Antimicrobial Agents and Chemotherapy|volume=39|issue=3|pages=577–585|issn=0066-4804|pmid=7793855|pmc=162587|doi=10.1128/aac.39.3.577}} Resistant strains were characterized by expression of methyltransferases which dimethylate residues within the 23S subunit of ribosomal RNA, preventing binding of macrolides, 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.{{Cite journal|last=Leclercq|first=Roland|date=February 2002|title=Mechanisms of Resistance to Macrolides and Lincosamides: Nature of the Resistance Elements and Their Clinical Implications|journal=Clinical Infectious Diseases|language=en|volume=34|issue=4|pages=482–492|doi=10.1086/324626|pmid=11797175|s2cid=14714107|issn=1058-4838|doi-access=free}} Nearly 40 erm genes have been reported to date, which are transferred primarily through plasmids and transposons.{{Cite journal|last1=Roberts|first1=Marilyn C.|last2=Sutcliffe|first2=Joyce|last3=Courvalin|first3=Patrice|last4=Jensen|first4=Lars Bogo|last5=Rood|first5=Julian|last6=Seppala|first6=Helena|date=1999-12-01|title=Nomenclature for Macrolide and Macrolide-Lincosamide-Streptogramin B Resistance Determinants|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=43|issue=12|pages=2823–2830|doi=10.1128/AAC.43.12.2823|issn=0066-4804|pmid=10582867|pmc=89572}}

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 isolated from hospital patients in Eastern Europe and North America were found to contain mutations in either 23S or other ribosomal protein genes.{{Cite journal|last1=Tait-Kamradt|first1=A.|last2=Davies|first2=T.|last3=Appelbaum|first3=P. C.|last4=Depardieu|first4=F.|last5=Courvalin|first5=P.|last6=Petitpas|first6=J.|last7=Wondrack|first7=L.|last8=Walker|first8=A.|last9=Jacobs|first9=M. R.|date=2000-12-01|title=Two New Mechanisms of Macrolide Resistance in Clinical Strains of Streptococcus pneumoniae from Eastern Europe and North America|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=44|issue=12|pages=3395–3401|doi=10.1128/AAC.44.12.3395-3401.2000|issn=0066-4804|pmid=11083646|pmc=90211}}

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.{{Cite journal|date=2017-06-01|title=Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps|journal=Biochemical Pharmacology|language=en|volume=133|pages=43–62|doi=10.1016/j.bcp.2016.10.005|pmid=27765485|issn=0006-2952|last1=Yılmaz|first1=Çiğdem|last2=Özcengiz|first2=Gülay|s2cid=25336534}} Staphylococci express efflux pumps with specificity for 14 and 15 member ring macrolides and streptogramin B, but not lincosamide molecules.{{Cite journal|last1=Sutcliffe|first1=J|last2=Tait-Kamradt|first2=A|last3=Wondrack|first3=L|date=August 1996|title=Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system.|journal=Antimicrobial Agents and Chemotherapy|volume=40|issue=8|pages=1817–1824|issn=0066-4804|pmid=8843287|pmc=163423|doi=10.1128/aac.40.8.1817}}

File:Triparitate_Complex.jpg

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.{{Cite journal|last1=Bozdogan|first1=Bülent|last2=Berrezouga|first2=Latifa|last3=Kuo|first3=Ming-Shang|last4=Yurek|first4=David A.|last5=Farley|first5=Kathleen A.|last6=Stockman|first6=Brian J.|last7=Leclercq|first7=Roland|date=1999-04-01|title=A New Resistance Gene, linB, Conferring Resistance to Lincosamides by Nucleotidylation in Enterococcus faecium HM1025|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=43|issue=4|pages=925–929|doi=10.1128/AAC.43.4.925|issn=0066-4804|pmid=10103201|pmc=89227}}

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.{{Cite news|url=https://www.merckvetmanual.com/pharmacology/antibacterial-agents/lincosamides|title=Lincosamides - Pharmacology - Merck Veterinary Manual|work=Merck Veterinary Manual|access-date=2018-11-10|language=en-US}}

Lincosamides have a broad distribution in several tissues, excluding cerebrospinal fluid. 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.{{Cite journal|last1=Osono|first1=T.|last2=Umezawa|first2=H.|date=July 1985|title=Pharmacokinetics of macrolides, lincosamides and streptogramins|journal=The Journal of Antimicrobial Chemotherapy|volume=16 Suppl A|pages=151–166|issn=0305-7453|pmid=3932301|doi=10.1093/jac/16.suppl_a.151}} Clindamycin accumulates in macrophages and other white blood cells, which can result in concentrations 50 times higher than plasma levels.{{Cite journal|last1=Johnson|first1=J. D.|last2=Hand|first2=W. L.|last3=Francis|first3=J. B.|last4=King-Thompson|first4=N.|last5=Corwin|first5=R. W.|date=March 1980|title=Antibiotic uptake by alveolar macrophages|journal=The Journal of Laboratory and Clinical Medicine|volume=95|issue=3|pages=429–439|issn=0022-2143|pmid=7354244}}

Lincosamides are often used clinically as an alternative antibiotic for patients who are allergic to penicillin. 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.{{Cite journal|date=2012-01-01|title=Antimicrobial agents|url=https://www.sciencedirect.com/science/article/pii/B9780702040894000202|journal=Medical Microbiology|language=en|pages=54–68|doi=10.1016/B978-0-7020-4089-4.00020-2|last1=Greenwood|first1=D.|last2=Irving|first2=W.L.|isbn=9780702040894}} 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,{{Cite journal|last1=Leyden|first1=J. J.|last2=Berger|first2=R. S.|last3=Dunlap|first3=F. E.|last4=Ellis|first4=C. N.|last5=Connolly|first5=M. A.|last6=Levy|first6=S. F.|date=2001|title=Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris|journal=American Journal of Clinical Dermatology|volume=2|issue=1|pages=33–39|doi=10.2165/00128071-200102010-00006|issn=1175-0561|pmid=11702619|s2cid=22486823}} toxic shock syndrome{{Cite journal|last1=Annane|first1=Djillali|last2=Clair|first2=Bernard|last3=Salomon|first3=Jérôme|date=August 2004|title=Managing toxic shock syndrome with antibiotics|journal=Expert Opinion on Pharmacotherapy|volume=5|issue=8|pages=1701–1710|doi=10.1517/14656566.5.8.1701|issn=1744-7666|pmid=15264985|s2cid=24494787}} and malaria,{{Cite journal|last1=Lell|first1=Bertrand|last2=Kremsner|first2=Peter G.|date=August 2002|title=Clindamycin as an Antimalarial Drug: Review of Clinical Trials|journal=Antimicrobial Agents and Chemotherapy|volume=46|issue=8|pages=2315–2320|doi=10.1128/AAC.46.8.2315-2320.2002|issn=0066-4804|pmid=12121898|pmc=127356}} and to decrease the risk of premature births in women with bacterial vaginosis.{{Cite journal|last=Lamont|first=Ronnie F.|date=March 2005|title=Can antibiotics prevent preterm birth--the pro and con debate|journal=BJOG: An International Journal of Obstetrics and Gynaecology|volume=112|issue=Suppl 1 |pages=67–73|doi=10.1111/j.1471-0528.2005.00589.x|issn=1470-0328|pmid=15715599|s2cid=25572794}} Lincosamide antibiotics may also be useful in the treatment of methicillin-resistant S. aureus.{{Cite web|url=http://www.pediatricsupersite.com/view.aspx?rid=35957|archive-url=https://web.archive.org/web/20111008040952/http://www.pediatricsupersite.com/view.aspx?rid=35957|archive-date=2011-10-08|title=Sitemap}}

File:Pseudomembranous_colitis_1.jpg

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.{{Cite news|url=https://www.merckvetmanual.com/pharmacology/antibacterial-agents/lincosamides|title=Lincosamides - Pharmacology - Merck Veterinary Manual|work=Merck Veterinary Manual|access-date=2018-11-23|language=en-US}}

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.{{Cite journal|last1=de Groot|first1=Mark C H|last2=van Puijenbroek|first2=Eugène P|date=October 2007|title=Clindamycin and taste disorders|journal=British Journal of Clinical Pharmacology|volume=64|issue=4|pages=542–545|doi=10.1111/j.1365-2125.2007.02908.x|issn=0306-5251|pmc=2048568|pmid=17635503}}

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

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

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

{{Reflist}}

{{Macrolides, lincosamides and streptogramins}}