Teicoplanin
Encyclopedia
Teicoplanin is an antibiotic
used in the prophylaxis and treatment of serious infections caused by Gram-positive
bacteria, including methicillin-resistant Staphylococcus aureus
and Enterococcus faecalis
. It is a glycopeptide
antibiotic extracted from Actinoplanes teichomyceticus
, with a similar spectrum of activity to vancomycin
. Its mechanism of action is to inhibit bacterial cell wall synthesis.
Teicoplanin is marketed by Sanofi-Aventis
under the trade name Targocid. It gained US FDA approval in 2009.
Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis
and Clostridium difficile
-associated diarrhoea, with comparable efficacy with vancomycin.
Its strength is considered to be due to the length of the hydrocarbon chain.
All teicoplanins share a same glycopeptide
core, termed teicoplanin A3-1 — a fused ring
structure to which two carbohydrate
s (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.
The structures of the teicoplanin core and the side-chains that characterize the five major teicoplanin compounds are 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]
The biosynthesis of the heptapeptide backbone is carried out by four nonribosomal peptide synthetases designated TeiA, TeiB, TeiC, and TeiD. Each of the modules has a domain for amino acid selection and activation as the aminoacyl-AMP. The catalytic domains in modules one and three of the nonribosomal peptide synthetase assembly line select and activate (S)-4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine. In addition to these modules for amino acid selection and activation, each module has a thiolation domain modified with phosphopantetheine to provide a thiol for covalent aminoacyl-S-enzyme formation.
Specific glycosylation has been shown to occur after the formation of the heptpeptide aglycone. Data suggests there are three separate glycosyl transferases required for the glycosylation of the teicoplanin aglycone. Two of these glycosyl transferases are involved in the addition of the N-fatty acyl-β-D-glucosamine and N-acetyl-β-D-glucosamine units. A third mannosyl transferase is responsible for the addition of the D-mannose unit onto residue 7. The fatty acyl chain is connected by amide bond to the glucosamine moiety by the action of an acyl transferase. In addition to glycosylation, it has been suggested that some genes code for deacetylases. In addition to the ability to salvage portions of the molecular structure, it provides a way to protect/deprotect the molecule.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
used in the prophylaxis and treatment of serious infections caused by Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria, including methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
and Enterococcus faecalis
Enterococcus faecalis
Enterococcus faecalis – formerly classified as part of the Group D Streptococcus system – is a Gram-positive, commensal bacterium inhabiting the gastrointestinal tracts of humans and other mammals. It is among the main constituents of some probiotic food supplements. Like other species in the genus...
. It is a glycopeptide
Glycopeptide
Glycopeptides are peptides that contain carbohydrate moieties covalently attached to the side chains of the amino acid residues that constitute the peptide. Over the past few decades it has been recognised that glycans on cell surface and those bound to proteins play a critical role in biology...
antibiotic extracted from Actinoplanes teichomyceticus
Actinoplanes
Actinoplanes are a genus in the family Actinoplanaceae. They have aerial mycelia and spherica, motile spores.Actinoplanes produces the pharmaceutically important compounds valienamine, teicoplanin and ramoplanin....
, with a similar spectrum of activity to vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
. Its mechanism of action is to inhibit bacterial cell wall synthesis.
Teicoplanin is marketed by Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
under the trade name Targocid. It gained US FDA approval in 2009.
Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
and Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
-associated diarrhoea, with comparable efficacy with vancomycin.
Its strength is considered to be due to the length of the hydrocarbon chain.
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).All teicoplanins share a same glycopeptide
Glycopeptide antibiotic
Glycopeptide antibiotics are a class of antibiotic drugs. The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin....
core, termed teicoplanin A3-1 — a fused ring
Macrocycle
A macrocycle is, as defined by IUPAC, "a cyclic macromolecule or a macromolecular cyclic portion of a molecule." In the chemical literature, organic chemists may consider any molecule containing a ring of nine or more atoms to be a macrocycle...
structure to which two carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s (mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
and N-acetylglucosamine
N-Acetylglucosamine
N-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid...
) are attached. The major and minor components also contain a third carbohydrate moiety — β-D-glucosamine
Glucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
— and differ only by the length and conformation of a side-chain attached to it.
The structures of the teicoplanin core and the side-chains that characterize the five major teicoplanin compounds are shown below.
Biosynthesis
Teicoplanin consists of a group of five structures. These structures possess a common aglycone, or core, consisting of seven amino acids that are 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 NMR. The studies indicate amino acids AA1, AA2, AA4, AA5, and AA6 are derived from tyrosine, and amino acids AA3 and AA7 are derived from acetate. To be specific, teicoplanin contains 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine residues, a chlorine atom attached on each of the tyrosine residues, and three sugar moieties, N-fatty 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 forty nine putative open reading frames (orf) 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. 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 Sequence | Regulatory Proteins | Other Enzymes | Resistant Enzymes | Β-hydroxy-tyrosine and 4-hydroxy-phenylglycin biosynthetic enzymes | Glycosyl Transferases | Peptide Synthetases | P450 Oxygenases | Halogenase | 3,5-dihydroxy phenylglycin biosynthetic enzymes |
| Genes | 11, 10, 3, 2, 15*, 16*, 31* | 9, 8, 1*, 2*, 4*, 11*, 13*, 21*, 26*, 27*, 30*, 32*, 33*, 34* | 7, 6, 5 | 4, 12*, 14*, 22*, 23*, 24*, 25*, 28*, 29* | 1, 3*, 10* | A, B, C, D | 5*, 6*, 7*, 9* | 8* | 17*, 18*, 19*, 20*, 23* |
Heptapeptide Backbone Synthesis
Analysis indicated tyrosine and three types of nonproteinogenic amino acids, (S)-4-hydroxyphenylglycine, 3,5-dihydroxyphenylglycine, and β-hydroxytyrosine as the building blocks of the teicoplanin group of glycopeptides. In all, six of the seven total amino acids of the teicoplanin backbone are composed of nonproteinogenic or modified amino acids. It has been found that eleven enzymes are coordinatively induced to produce these six required residues. Teicoplanin contains two chlorinated positions on teicoplanin, 2 (3-Cl-Tyr) and 6 (3-Cl-β-Hty). It has been proposed that the putative halogenase Orf8* catalyzes the halogenation on both amino acids. It is thought chlorination occurs at a very early point in the biosynthesis prior to phenolic oxidative coupling, with the possibility of tyrosine or β-hydroxytyrosine being the substrate of chlorination.The biosynthesis of the heptapeptide backbone is carried out by four nonribosomal peptide synthetases designated TeiA, TeiB, TeiC, and TeiD. Each of the modules has a domain for amino acid selection and activation as the aminoacyl-AMP. The catalytic domains in modules one and three of the nonribosomal peptide synthetase assembly line select and activate (S)-4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine. In addition to these modules for amino acid selection and activation, each module has a thiolation domain modified with phosphopantetheine to provide a thiol for covalent aminoacyl-S-enzyme formation.
Post-Heptapeptide Backbone Formation Modification
Once the heptapeptide backbone has been formed, the cylcization of the linear structure is begun. Gene disruption studies indicate a cytochrome P450 oxygenase as the enzyme that performs the coupling reactions. OxyB has been suggested to form the first ring by coupling residues 4 and 6. OxyA then couples residues 2 and 4, followed by the formation of a C-C bond between residues 5 and 7 by OxyC. A fourth enzyme catalyzes the coupling of residues 1 and 3, although where this coupling fits into the OxyB/OxyA/OxyC order is not known. It has been suggested that the regioselectivity and atropisomer selectivity of these probable one-electron coupling reactions is due to the folding and orientation requirements of the partially crossed-linked substrates in the enzyme active site. The coupling reactions are shown below.