Teicoplanin

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Teicoplanin
Teicoplanin core and major components.svg
Clinical data
Pronunciation /ˌtaɪkoʊˈpleɪnɪn/
TY-koh-PLAY-nin
Trade names Targocid
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:B3
Routes of
administration 		Intravenous, intramuscular
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only)
  • EU:Rx-only [2]
Pharmacokinetic data
Bioavailability 90% (given IM)
Protein binding 90% to 95%
Metabolism Nil
Elimination half-life 70 to 100 hours
Excretion Kidney (97% unchanged)
Identifiers
  • Ristomycin A 34-O-[2-(acetylamino)-2-deoxy-.beta.-D-glucopyranosyl]-22,31-dichloro-7-demethyl-64-O-demethyl-19-deoxy-56-O-[2-deoxy-2-[(8-methyl-1-oxononyl)amino]-.beta.-D-glucopyranosyl]-42-O-.alpha.-D-mannopyranosyl-
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
Chemical and physical data
Formula Variable
Molar mass 1564.3 to 1907.7 g/mol
Melting point 260 °C (500 °F) (dec.)
  • InChI=1S/C89H99Cl2N9O33/c1-34(2)9-7-5-4-6-8-10-61(109)95-69-75(114)72(111)59(32-102)130-88(69)133-79-56-26-41-27-57(79)127-53-18-14-39(24-48(53)91)78(132-87-68(93-35(3)104)74(113)71(110)58(31-101)129-87)70-85(122)99-67(86(123)124)46-29-43(106)30-55(128-89-77(116)76(115)73(112)60(33-103)131-89)62(46)45-23-38(13-15-50(45)107)64(82(119)100-70)97-84(121)66(41)98-83(120)65-40-21-42(105)28-44(22-40)125-54-25-37(12-16-51(54)108)63(92)81(118)94-49(80(117)96-65)20-36-11-17-52(126-56)47(90)19-36/h11-19,21-30,34,49,58-60,63-78,87-89,101-103,105-108,110-116H,4-10,20,31-33,92H2,1-3H3,(H,93,104)(H,94,118)(H,95,109)(H,96,117)(H,97,121)(H,98,120)(H,99,122)(H,100,119)(H,123,124)/t49-,58-,59-,60-,63+,64-,65+,66-,67-,68-,69-,70+,71-,72-,73-,74-,75-,76+,77+,78-,87+,88+,89+/m1/s1 Yes check.svgY
  • Key:FHBQKTSCJKPYIO-OXIGXJDJSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall [3] peptidoglycan [4] synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis . [3]

Contents

Teicoplanin is marketed by Sanofi-Aventis under the trade name Targocid. Other trade names include Ticocin marketed by Cipla(India).

Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis and Clostridium difficile -associated diarrhoea, with comparable efficacy with vancomycin. [5]

Its strength is considered to be due to the length of the hydrocarbon chain. [6]

Teicoplanin is produced by so-called "rare" actinobacterium Actinoplanes teichomyceticus ATCC 31121, [7] belonging to the Micromonosporaceae family. Biosynthetic pathway leading to teicoplanin, as well as the regulatory circuit governing the biosynthesis, were studied intensively in recent years allowing to construct an integrated model of the biosynthesis. [8]

Indications

Teicoplanin is applicable in treatment of a wide range of infections with Gram-positive bacteria, including endocarditis, septicaemia, soft tissue and skin infections, and venous catheter-associated infections. [9]

Susceptible organisms

Teicoplanin has demonstrated in vitro efficacy against Gram-positive bacteria including staphylococci (including MRSA), streptococci, enterococci, and against anaerobic Gram-positive bacteria including Clostridium spp. Teicoplanin is not effective against Gram-negative bacteria as the large, polar molecules of the compound are unable to pass through the external membrane of these organisms. [9] The following represents MIC susceptibility data for a few medically significant pathogens: [4]

Pharmacology

Teicoplanin exhibits a very long biological half-life of about 45-70h (sufficient plasma levels can thus be sustained with once-daily administration). Elimination is almost exclusively renal. It is mostly excreted unchanged. [9]

Adverse effects

Adverse effects of teicoplanin are usually limited to local effects or hypersensitivity reactions. While there is potenial for nephrotoxicity and ototoxicity, incidence of such organ toxicity is rare if recommended serum concentrations are successfully maintained. [9]

Considerations

Reduced renal function slows teicoplanin clearance, consequently increasing its elimination half-life. Elimination half-life is longer in the elderly due to the reduced renal function in this population. [9]

Chemistry

Teicoplanin (TARGOCID, marketed by Sanofi Aventis Ltd) is actually a mixture of several compounds, five major (named teicoplanin A2-1 through A2-5) and four minor (named teicoplanin RS-1 through RS-4). [10] [11] All teicoplanins share a same glycopeptide core, termed teicoplanin A3-1 — a fused ring structure to which two carbohydrates (mannose and N-acetylglucosamine) are attached. The major and minor components also contain a third carbohydrate moiety — β-D-glucosamine — and differ only by the length and conformation of a side-chain attached to it. Teicoplanin A2-4 and RS-3 have chiral side chains while all other side chains are achiral. Teicoplanin A3 lacks both the side chains as well as the β-D-glucosamine moiety.

The structures of the teicoplanin core and the side-chains that characterize the five major as well as four minor teicoplanin compounds are shown below.

Teicoplanin core (left, black) and side-chains that characterize teicoplanins A2-1 through A2-5 (middle) as well as related RS-1 through RS-4 (right). In blue: b-D-glucosamine. Teicoplanin core components.svg
Teicoplanin core (left, black) and side-chains that characterize teicoplanins A2-1 through A2-5 (middle) as well as related RS-1 through RS-4 (right). In blue: β-D-glucosamine.

Teicoplanin refers to a complex of related natural products isolated from the fermentation broth of a strain of Actinoplanes teichomyceticus , [12] consisting of a group of five structures. These structures possess a common aglycone, or core, consisting of seven amino acids bound by peptide and ether bonds to form a four-ring system. These five structures differ by the identity of the fatty acyl side-chain attached to the sugar. The origin of these seven amino acids in the biosynthesis of teicoplanin was studied by 1H and 13C nuclear magnetic resonance. [13] The studies indicate amino acids 4-Hpg, 3-Cl-Tyr, and 3-chloro-β-hydroxytyrosine are derived from tyrosine, and the amino acid 3,5-dihydroxyphenylglycine (3,5-Dpg) is derived from acetate. Teicoplanin contains 6 non-proteinogenic amino acids and three sugar moieties, N-acyl-β-D-glucosamine, N-acetyl-β-D-glucosamine, and D-mannose.

Gene cluster

The study of the genetic cluster encoding the biosynthesis of teicoplanin identified 49 putative open reading frames (ORFs) involved in the compound's biosynthesis, export, resistance, and regulation. Thirty-five of these ORFs are similar to those found in other glycopeptide gene clusters. The function of each of these genes is described by Li and co-workers. [14] A summary of the gene layout and purpose is shown below.

Gene layout. The genes are numbered. The letters L and R designate transcriptional direction. The presence of the * symbol means a gene is found after NRPs, which are represented by A, B, C, and D. Based on the figure from: Li, T-L.; Huang, F.; Haydock, S. F.; Mironenko, T.; Leadlay, P. F.; Spencer, J. B. Chemistry & Biology. 2004, 11, p. 109.

[11-L] [10-L] [9-R] [8-R] [7-R] [6-R] [5-R] [4-L][3-L] [2-L] [1-R] [A-R] [B-R] [C-R] [D-R] [1*-R] [2*-R] [3*-R] [4*-R] [5*-R] [6*-R] [7*-R] [8*-R] [9*-R] [10*-R] [11*-R] [12*-R] [13*-R] [14*-R] [15*-R] [16*-R] [17*-R] [18*-R] [19*-R] [20*-R] [21*-R] [22*-R] [23*-R] [24*-R] [25*-L] [26*-L] [27*-R] [28*-R] [29*-R] [30*-R][31*-R] [32*-L] [33*-L] [34*-R]

Enzyme produced by gene sequenceRegulatory proteinsOther enzymesResistant enzymesΒ-hydroxy-tyrosine and 4-hydroxy-phenylglycin biosynthetic enzymesGlycosyl transferasesPeptide synthetasesP450 oxygenasesHalogenase3,5-dihydroxy phenylglycin biosynthetic enzymes
Genes11, 10, 3, 2, 15*, 16*, 31*9, 8, 1*, 2*, 4*, 11*, 13*, 21*, 26*, 27*, 30*, 32*, 33*, 34*7, 6, 54, 12*, 14*, 22*, 23*, 24*, 25*, 28*, 29*1, 3*, 10*A, B, C, D5*, 6*, 7*, 9*8*17*, 18*, 19*, 20*, 23*

Heptapeptide backbone synthesis

The heptapeptide backbone of teicoplanin is assembled by the nonribosomal peptide synthetases (NRPSs) TeiA, TeiB, TeiC and TeiD. Together these comprise seven modules, each containing a number of domains, with each module responsible for the incorporation of a single amino acid. Modules 1, 4, and 5 activate L-4-Hpg as the aminoacyl-AMP, modules 2 and 6 activate L-Tyr, and modules 3 and 7 activate L-3,5-Dpg. The activated amino acids are covalently bound to the NRPS as thioesters by a phosphopantetheine cofactor, which is attached to the peptidyl carrier protein (PCP) domain. The enzyme bound amino acids are then joined by amide bonds by the action of the condensation (C) domain.

The heptapetide of teicoplanin contains 4 D-amino acids, formed by epimerization of the activated L-amino acids. Modules 2, 4 and 5 each contain an epimerization (E) domain which catalyzes this change. Module 1 does not contain an E domain, and epimerization is proposed to be catalysed by the C domain. [15] In all, six of the seven total amino acids of the teicoplanin backbone are composed of nonproteinogenic or modified amino acids. Eleven enzymes are coordinatively induced to produce these six required residues. [16] Teicoplanin contains two chlorinated positions, 2 (3-Cl-Tyr) and 6 (3-Cl-β-Hty). The halogenase Tei8* has been acts to catalyze the halogenation of both tyrosine residues. Chlorination occurs at the amino acyl-PCP level during the biosynthesis, prior to phenolic oxidative coupling, with the possibility of tyrosine or β-hydroxytyrosine being the substrate of chlorination. [17] Hydroxylation of the tyrosine residue of module 6 also occurs in trans during the assembly of the heptapeptide backbone.

Modification after heptapeptide backbone formation

Once the heptapeptide backbone has been formed, the linear enzyme-bound intermediate is cyclized. [16] Gene disruption studies indicate cytochrome P450 oxygenases as the enzymes that performs the coupling reactions. The X-domain in the final NRPS module is required to recruit the oxygenase enzymes. [18] OxyB forms the first ring by coupling residues 4 and 6, and OxyE then couples residues 1 and 3. OxyA couples residues 2 and 4, followed by the formation of a C-C bond between residues 5 and 7 by OxyC. [19] The regioselectivity and atropisomer selectivity of these probable one-electron coupling reactions has been suggested to be due to the folding and orientation requirements of the partially crossed-linked substrates in the enzyme active site. [16] The coupling reactions are shown below.

Oxidative cross-linkings steps during teicoplanin biosynthesis, catalysed by cytochrome P450 oxidases OxyB, E, A and C. Teicoplanin P450 Oxidations.png
Oxidative cross-linkings steps during teicoplanin biosynthesis, catalysed by cytochrome P450 oxidases OxyB, E, A and C.

Specific glycosylation has been shown to occur after the formation of the heptpeptide aglycone. [20] Three separate glycosyl transferases are required for the glycosylation of the teicoplanin aglycone. Tei10* catalyses the addition of GlcNAc to residue 4, followed by deacetylation by Tei2*. The acyl chain (produced by the action of Tei30* and Tei13*) is then added by Tei11*. Tei1 then adds a second GlcNAc to the β-hydroxyl group of residue 6, followed by mannosylation of residue 7 catalysed by Tei3*. [21]

Related Research Articles

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

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References

  1. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. ↑ Human Medicines Evaluation Division (10 December 2020). "Active substance: teicoplanin" (PDF). List of nationally authorised medicinal products. European Medicines Agency.
  3. 1 2 Reynolds PE (November 1989). "Structure, biochemistry and mechanism of action of glycopeptide antibiotics". European Journal of Clinical Microbiology & Infectious Diseases. 8 (11): 943–950. doi:10.1007/BF01967563. PMID   2532132. S2CID   21551939.
  4. 1 2 "Teicoplanin Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). TOKU-E.
  5. ↑ de Lalla F, Nicolin R, Rinaldi E, Scarpellini P, Rigoli R, Manfrin V, et al. (October 1992). "Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea". Antimicrobial Agents and Chemotherapy. 36 (10): 2192–2196. doi:10.1128/AAC.36.10.2192. PMC   245474 . PMID   1444298.
  6. ↑ Gilpin M, Milner P (1997). "Resisting changes -- Over the past 40 years the glycopeptide antibiotics have played a crucial role in treating bacterial infections. But how long can it continue ?". Royal Society of Chemistry. Archived from the original on 2002-12-21. Retrieved 2006-10-15. - includes picture of Teicoplanin's structure.
  7. ↑ "Actinoplanes teichomyceticus Parenti et al". ATCC (American Type Culture Collection).
  8. ↑ Yushchuk O, Ostash B, Truman AW, Marinelli F, Fedorenko V (April 2020). "Teicoplanin biosynthesis: unraveling the interplay of structural, regulatory, and resistance genes". Applied Microbiology and Biotechnology. 104 (8): 3279–3291. doi:10.1007/s00253-020-10436-y. PMID   32076781. S2CID   211170874.
  9. 1 2 3 4 5 Campoli-Richards DM, Brogden RN, Faulds D (1990-09-01). "Teicoplanin". Drugs. 40 (3): 449–486. doi:10.2165/00003495-199040030-00007. ISSN   1179-1950. PMID   2146108. S2CID   195699141.
  10. ↑ Bernareggi A, Borghi A, Borgonovi M, Cavenaghi L, Ferrari P, Vékey K, et al. (August 1992). "Teicoplanin metabolism in humans". Antimicrobial Agents and Chemotherapy. 36 (8): 1744–1749. doi:10.1128/AAC.36.8.1744. PMC   192040 . PMID   1416858.
  11. ↑ Geibel C, Olfert M, Knappe C, Serafimov K, Lämmerhofer M (February 2023). "Branched medium-chain fatty acid profiling and enantiomer separation of anteiso-forms of teicoplanin fatty acyl side chain RS3 using UHPLC-MS/MS with polysaccharide columns". Journal of Pharmaceutical and Biomedical Analysis. 224: 115162. doi:10.1016/j.jpba.2022.115162. PMID   36423498. S2CID   253529204.
  12. ↑ Jung HM, Jeya M, Kim SY, Moon HJ, Kumar Singh R, Zhang YW, et al. (September 2009). "Biosynthesis, biotechnological production, and application of teicoplanin: current state and perspectives". Applied Microbiology and Biotechnology. 84 (3): 417–428. doi:10.1007/s00253-009-2107-4. PMID   19609520. S2CID   45038487.
  13. ↑ Heydorn A, Petersen BO, Duus JO, Bergmann S, Suhr-Jessen T, Nielsen J (March 2000). "Biosynthetic studies of the glycopeptide teicoplanin by (1)H and (13)C NMR". The Journal of Biological Chemistry. 275 (9): 6201–6206. doi: 10.1074/jbc.275.9.6201 . PMID   10692413.
  14. ↑ Li TL, Huang F, Haydock SF, Mironenko T, Leadlay PF, Spencer JB (January 2004). "Biosynthetic gene cluster of the glycopeptide antibiotic teicoplanin: characterization of two glycosyltransferases and the key acyltransferase". Chemistry & Biology. 11 (1): 107–119. doi: 10.1016/j.chembiol.2004.01.001 . PMID   15113000.
  15. ↑ Kaniusaite M, Tailhades J, Kittilä T, Fage CD, Goode RJ, Schittenhelm RB, et al. (January 2021). "Understanding the early stages of peptide formation during the biosynthesis of teicoplanin and related glycopeptide antibiotics". The FEBS Journal. 288 (2): 507–529. doi: 10.1111/febs.15350 . PMID   32359003. S2CID   218481859.
  16. 1 2 3 Kahne D, Leimkuhler C, Lu W, Walsh C (February 2005). "Glycopeptide and lipoglycopeptide antibiotics". Chemical Reviews. 105 (2): 425–448. doi:10.1021/cr030103a. PMID   15700951.
  17. ↑ Kittilä T, Kittel C, Tailhades J, Butz D, Schoppet M, Büttner A, et al. (September 2017). "Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis". Chemical Science. 8 (9): 5992–6004. doi:10.1039/C7SC00460E. PMC   5620994 . PMID   28989629.
  18. ↑ Haslinger K, Peschke M, Brieke C, Maximowitsch E, Cryle MJ (May 2015). "X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis". Nature. 521 (7550): 105–109. Bibcode:2015Natur.521..105H. doi:10.1038/nature14141. PMID   25686610. S2CID   4466657.
  19. ↑ Peschke M, Brieke C, Cryle MJ (October 2016). "F-O-G Ring Formation in Glycopeptide Antibiotic Biosynthesis is Catalysed by OxyE". Scientific Reports. 6 (1): 35584. Bibcode:2016NatSR...635584P. doi:10.1038/srep35584. PMC   5067714 . PMID   27752135.
  20. ↑ Kaplan J, Korty BD, Axelsen PH, Loll PJ (May 2001). "The role of sugar residues in molecular recognition by vancomycin". Journal of Medicinal Chemistry. 44 (11): 1837–1840. doi:10.1021/jm0005306. PMID   11356118.
  21. ↑ Yushchuk O, Ostash B, Pham TH, Luzhetskyy A, Fedorenko V, Truman AW, et al. (August 2016). "Characterization of the Post-Assembly Line Tailoring Processes in Teicoplanin Biosynthesis". ACS Chemical Biology. 11 (8): 2254–2264. doi:10.1021/acschembio.6b00018. PMID   27285718.
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