teicoplanin

テイコプラニン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/10 14:51:05」(JST)

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Teicoplanin

Systematic (IUPAC) name
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-
Clinical data
Trade names	Targocid
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	B3 (AU)
Legal status	POM (UK)
Routes	Intravenous, intramuscular
Pharmacokinetic data
Bioavailability	90% (given IM)
Protein binding	90% to 95%
Metabolism	Nil
Half-life	70 to 100 hours
Excretion	Renal (97% unchanged)
Identifiers
CAS number	61036-62-2 Y
ATC code	J01XA02
PubChem	CID 16129712
DrugBank	DB06149
ChemSpider	16736197 Y
UNII	4U3D3YY81M Y
KEGG	D02142 Y
ChEMBL	CHEMBL415428 N
NIAID ChemDB	007693
Chemical data
Formula	Variable
Mol. mass	1564.3 to 1907.7 g/mol
InChI 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 Y Key:FHBQKTSCJKPYIO-OXIGXJDJSA-N Y
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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 semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall synthesis.

Teicoplanin is marketed by Sanofi-Aventis under the trade name Targocid.

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.

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 R_S-1 through R_S-4). 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.

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

Teicoplanin core (left, black) and side-chains that characterize teicoplanins A₂-1 through A₂-5 (right). In blue: β-D-glucosamine.

Biosynthesis

The antibiotic Teicoplanin refers to a complex of related natural products isolated from the fermentation broth of a strain of Actinoplanes teichomyceticus, consisting 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.

Oxidative Coupling Of Teicoplanin Backbone

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.

References

UpToDate Contents

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• 1. 成人における侵襲性メチシリン耐性黄色ブドウ球菌感染症の治療 treatment of invasive methicillin resistant staphylococcus aureus infections in adults
• 2. カテーテル関連血流感染症の治療のための抗菌薬ロック療法 antibiotic lock therapy for treatment of catheter related bloodstream infections
• 3. バンコマイシン過敏症 vancomycin hypersensitivity
• 4. 腸球菌感染症の治療 treatment of enterococcal infections
• 5. 固有弁心内膜炎の抗菌療法 antimicrobial therapy of native valve endocarditis

English Journal

• Methicillin-resistant Staphylococcus aureus in the western region of Saudi Arabia: prevalence and antibiotic susceptibility pattern.

• El Amin NM, Faidah HS.SourceDr. Nagwa Mustafa El Amin, Faculty of Medicine, Umm Al Qura University, 715 Makkah, Saudi Arabia, nagwaelamin@yahoo.com.
• Annals of Saudi medicine.Ann Saudi Med.2012 Sep;32(5):513-6.
• BACKGROUND AND OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) emerged in 1960 and was a problem confined largely to the healthcare setting, or hospital-associated MRSA (HA-MRSA). In the 1990s, community-associated MRSA (CA-MRSA) infections appeared. In Saudi Arabia, the prevalence of
• PMID 22871621

• Lack of upward creep of glycopeptide MICs for methicillin-resistant Staphylococcus aureus (MRSA) isolated in the UK and Ireland 2001-07.

• Reynolds R, Hope R, Warner M, Macgowan AP, Livermore DM, Ellington MJ; on behalf of the BSAC Extended Working Party on Resistance Surveillance.SourceDepartment of Medical Microbiology, Southmead Hospital, Bristol BS10 5NB, UK.
• The Journal of antimicrobial chemotherapy.J Antimicrob Chemother.2012 Aug 16. [Epub ahead of print]
• OBJECTIVES: There have been several reports of upward creep in vancomycin MICs for Staphylococcus aureus [predominantly methicillin-resistant S. aureus (MRSA)] over recent years, but only in single centres or using contemporaneous results. We aimed to test the hypothesis of MIC creep in a multicentr
• PMID 22899805

Japanese Journal

• Comparative Prevalence of Antibiotic Resistance, Staphylococcal Cassette Chromosome Mec and Superantigenic Toxin Genes in Coagulase-Negative Staphylococci

• Abe Yukiko,Hu Dong-Liang,Omoe Katsuhiko,Fukuda Ikuo,Nakane Akio
• 弘前医学 63(2-4), 143-153, 2012-11-30
• … The isolates with type I or IVa gene showed highly resistance to clindamycin and gentamicin, the isolates with type II showed more resistance to teicoplanin, the isolates with type III or type V showed more resistance to clindamycin. …
• NAID 120004994682

• 多剤耐性グラム陽性菌治療薬 (特集 新しい治療薬と呼吸器感染症診療の展開)

• 大曲 貴夫
• 日本胸部臨床 71(9), 859-865, 2012-09-00
• NAID 40019422682

Related Links

• Teicoplanin - Wikipedia, the free 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 lipopeptide antibiotic and it is ...

• teicoplanin Drug Information | MIMS.com USA

teicoplanin: IV/IM Susceptible infections Initial: 6 mg/kg on the 1st day, then 3 mg/ kg/day. Severe infection: 6 mg/kg 12 hrly for the 1st 3 doses, then 6.

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★リンクテーブル★

リンク元	「テイコプラニン」「TEIC」

「テイコプラニン」

　　[★]

英

teicoplanin, TEIC

商

タゴシッド

関

抗菌薬、グリコペプチド系抗菌薬

• MRSAに対して用いる。アンピシリン耐性の腸球菌属にも用いる
• 作用機序は細胞壁合成阻害であり、バンコマイシンと同様。
• 腎排泄型

「TEIC」

　　[★] テイコプラニン teicoplanin