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antibiotic (trade name Kantrex) used to treat severe infections (同)Kantrex

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/06 06:38:03」(JST)

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Kanamycin (also known as kanamycin A) is an aminoglycoside bacteriocidal antibiotic, available in oral, intravenous, and intramuscular forms, and used to treat a wide variety of infections. Kanamycin is isolated from the bacterium Streptomyces kanamyceticus^[1] and its most commonly used form is kanamycin sulfate.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.^[2]

Medical uses

Spectrum of activity

Kanamycin has been used to treat infections caused by Gram-negative bacteria including E. coli, Proteus spp., Serratia marcescens, and Klebsiella pneumoniae. The following represents MIC susceptibility data for a few medically significant pathogens:

Escherichia coli - 0.05 μg/ml - >512 μg/ml
Klebsiella pneumoniae - 7.5 μg/ml - 128 μg/ml

^[3]

Side effects

Serious side effects include tinnitus or loss of hearing, toxicity to kidneys, and allergic reactions to the drug.^[4]

Mechanism

Kanamycin interacts with the 30S subunit of prokaryotic ribosomes. It gives birth to substantial amounts of mistranslation and indirectly inhibits translocation during protein synthesis.^[5]^[6]

Composition

Kanamycin is a mixture of three main components: kanamycin A, B, and C. Kanamycin A is the major component in kanamycin.^[7] The effects of these components do not appear to be widely studied as individual compounds when used against prokaryotic and eukaryotic cells.

Biosynthesis

While the main product produced by Streptomyces kanamyceticus is kanamycin A, additional products are also produced, including kanamycin B, kanamycin C, kanamycin D and kanamycin X.

The kanamycin biosynthetic pathway can be divided into two parts. The first part is common to several aminoglycoside antibiotics, such as butirosin and neomycin. In it a unique aminocyclitol, 2-deoxystreptamine, is biosynthesized from D-glucopyranose 6-phosphate in four steps. At this point the kanamycin pathway splits into two branches due to the promiscuity of the next enzyme, which can utilize two different glycosyl donors - UDP-N-acetyl-α-D-glucosamine and UDP-α-D-glucose. One of the branches forms kanamycin C and kanamycin B, while the other branch forms kanamycin D and kanamycin X. However, both kanamycin B and kanamycin D can be converted to kanamycin A, so both branches of the pathway converge at kanamycin A.^[8]

Use in research

Kanamycin is used in molecular biology as a selective agent most commonly to isolate bacteria (e.g., E. coli) which have taken up genes (e.g., of plasmids) coupled to a gene coding for kanamycin resistance (primarily Neomycin phosphotransferase II [NPT II/Neo]). Bacteria that have been transformed with a plasmid containing the kanamycin resistance gene are plated on kanamycin (50-100 ug/ml) containing agar plates or are grown in media containing kanamycin (50-100 ug/ml). Only the bacteria that have successfully taken up the kanamycin resistance gene become resistant and will grow under these conditions. As a powder, kanamycin is white to off-white and is soluble in water (50 mg/ml).

At least one such gene, Atwbc19^[9] is native to a plant species, of comparatively large size and its coded protein acts in a manner which decreases the possibility of horizontal gene transfer from the plant to bacteria; it may be incapable of giving resistance to bacteria even if gene transfer occurs.

The KanMX marker

The selection marker kanMX is a hybrid gene consisting of a bacterial aminoglycoside phosphotransferase (kan^r from transposon Tn903) under control of the strong TEF promoter from Ashbya gossypii.^[10]^[11]

Mammalian cells, yeast, and other eukaryotes acquire resistance to geneticin (= G418, an aminoglycoside antibiotic similar to kanamycin) when transformed with a kanMX marker. In yeast, the kanMX marker avoids the requirement of auxotrophic markers. In addition, the kanMX marker renders E. coli resistant to kanamycin. In shuttle vectors the KanMX cassette is used with an additional bacterial promoter. Several versions of the kanMX cassette are in use, e.g. kanMX1-kanMX6. They primarily differ by additional restriction sites and other small changes around the actual open reading frame.^[10]^[12]

References

^ Garrod, L.P., et al.: "Antibiotic and Chemotherapy", page 131. Churchill Livingstone, 1981
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ http://antibiotics.toku-e.com/antimicrobial_744_6.html
^ Consumer Drug Information: Kanamycin, 2 April 2008, retrieved 2008-05-04
^ Pestka, S.: "The Use of Inhibitors in Studies on Protein Synthesis", Methods in Enzymology 30, pp.261-282, 1975
^ Misumi, M. & Tanaka, N.: "Mechanism of Inhibition of Translocation by Kanamycin and Viomycin: A Comparative Study with Fusidic Acid, Biochem.Biophys.Res.Commun. 92, pp.647-654, 1980
^ United States. National Institutes of Health. Kanamycin Compound Summary. PubChem. Web. 21 Aug. 2012.
^ "kanamycin biosynthesis pathway in MetaCyc". MetaCyc.org. Retrieved 30 September 2014.
^ "Horizontal Gene Transfer: Plant vs. Bacterial Genes for Antibiotic Resistance Scenario's—What's the Difference?". Isb.vt.edu. Retrieved 2013-06-24.
^ ^a ^b Wach, A.; Brachat, A.; Pöhlmann, R.; Philippsen, P. (1994). "New heterologous modules for classical or PCR-based gene disruptions in Saccharomyces cerevisiae". Yeast 10 (13): 1793–1808. doi:10.1002/yea.320101310. PMID 7747518.
^ Steiner, S.; Philippsen, P. (1994). "Sequence and promoter analysis of the highly expressed TEF gene of the filamentous fungus Ashbya gossypii". Molecular & general genetics : MGG 242 (3): 263–271. doi:10.1007/BF00280415. PMID 8107673.
^ Wach, A. (1996). "PCR-synthesis of marker cassettes with long flanking homology regions for gene disruptions in S. Cerevisiae". Yeast 12 (3): 259–265. doi:10.1002/(SICI)1097-0061(19960315)12:3<259::AID-YEA901>3.0.CO;2-C. PMID 8904338.

External links

From kanamycin-evopure.com:
- Technical Information
- Purity Survey
- Toxicity Data
- Working Concentrations
- Kanamycin Impurities

UpToDate Contents

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English Journal

Phytopharmacological evaluation of ethanol extract of Sida cordifolia L. roots.

Momin MA, Bellah SF, Rahman SM, Rahman AA, Murshid GM, Emran TB.SourceDepartment of Pharmacy, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh. Electronic address: talhabmb@gmail.com.
Asian Pacific journal of tropical biomedicine.Asian Pac J Trop Biomed.2014 Jan;4(1):18-24. doi: 10.1016/S2221-1691(14)60202-1.
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Efficient and simple generation of unmarked gene deletions in Mycobacterium smegmatis.

Shenkerman Y, Elharar Y, Vishkautzan M, Gur E.SourceDepartment of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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Pattern of induction of colicin E9 synthesis by sub MIC of Norfloxacin antibiotic.

Bano S, Vankemmelbeke M, Penfold CN, James R.SourceSchool of Molecular Medical Sciences, Centre for Biomolecular Sciences, University of Nottingham, University Park, NG7 2RD, United Kingdom; Department of Microbiology, University of Sindh, Jamshoro, Pakistan. Electronic address: microhira@hotmail.com.
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PMID 23669239

Japanese Journal

A new series of activation-tagging vectors : pKANACB, pKANACK and pKANACH

SHIMIZU Keiichi,HASHIMOTO Fumio,清水圭一,橋本文雄
鹿兒島大學農學部學術報告=Bulletin of the Faculty of Agriculture, Kagoshima University 63, 39-47, 2013-03-29
… tumefaciens strain AGLO harboring the activation-tagging vectors (AGL0pKANACB, AGL0-pKANACK and AGL0-pKANACH), glufosinate-, kanamycin- and hygromycinresistantplants, respectively, were generated. …
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Related Pictures

★リンクテーブル★

リンク元	「アミノグリコシド系抗菌薬」「カナマイシン」「kanamycin monosulfate」
拡張検索	「dideoxykanamycin B」「bekanamycin sulfate」「kanamycin resistance」

「アミノグリコシド系抗菌薬」

Kanamycin
Systematic (IUPAC) name
	2-(aminomethyl)- 6-[4,6-diamino-3- [4-amino-3,5-dihydroxy-6-(hydroxymethyl) tetrahydropyran-2-yl]oxy- 2-hydroxy- cyclohexoxy]- tetrahydropyran- 3,4,5-triol
Clinical data
AHFS/Drugs.com	monograph
Pregnancy; category	D;
Routes of; administration	Oral, intravenous, intramuscular
Legal status
Legal status	?;
Pharmacokinetic data
Bioavailability	very low after oral delivery
Metabolism	Unknown
Biological half-life	2 hours 30 minutes
Excretion	Urine (as unchanged drug)
Identifiers
CAS Number	59-01-8
ATC code	A07AA08 (WHO) J01GB04 (WHO) S01AA24 (WHO)
PubChem	CID 6032
DrugBank	DB01172
ChemSpider	5810
UNII	RUC37XUP2P
ChEBI	CHEBI:17630
ChEMBL	CHEMBL1384
PDB ligand ID	KAN (PDBe, RCSB PDB)
Chemical data
Formula	C18H36N4O11
Molar mass	484.499
	SMILES O([C@@H]2[C@@H](O)[C@H](O[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](N)C[C@H]2N)[C@H]3O[C@@H]([C@@H](O)[C@H](N)[C@H]3O)CO ;
	InChI InChI=1S/C18H36N4O11/c19-2-6-10(25)12(27)13(28)18(30-6)33-16-5(21)1-4(20)15(14(16)29)32-17-11(26)8(22)9(24)7(3-23)31-17/h4-18,23-29H,1-3,19-22H2/t4-,5+,6-,7-,8+,9-,10-,11-,12+,13-,14-,15+,16-,17-,18-/m1/s1 ; Key:SBUJHOSQTJFQJX-NOAMYHISSA-N ;
(verify)

　　[★]

英: aminoglycoside antibiotic
関: 抗菌薬、アミノグリコシド系薬、アミノグリコシド

GOO. chapter.45

タンパク質合成阻害による抗菌薬は静菌的なのもが多いが、アミノグリコシド系抗菌薬は「殺菌的」に作用

構造

amino sugars linked to an aminocyclitol ring by glycosidic bonds (GOO.1155)
名前の通りアミノ基-NH₂を多数有しているため正電荷を帯びる

→経口吸収不良

→脳脊髄液に移行しにくい。

→腎排泄されやすい

動態

内服不可能→外来患者に使いにくい
細胞膜(内膜)の通過は膜電位ポテンシャルに依存している。ここが律速段階となる。　→　細胞内移行性悪

阻害、拮抗要素：二価陽イオン、高浸透圧、pHの低下、嫌気的条件

膿瘍など嫌気的条件、酸性の高浸透圧尿など細菌の膜電位ポテンシャルが低下する場合に薬効低下

作用機序

30Sリボソームに作用してタンパク質合成を阻害

1. 翻訳開始を阻害
2. 翻訳を停止させる
3. 誤ったアミノ酸を取り込ませる

異常蛋白が細胞膜に挿入され、膜の透過性を変えてさらにアミノグリコシド系抗菌薬の取り込みを促す

薬理作用

薬効は迅速。濃度依存的。
post-antibiotic effectがある。

抗菌薬の血漿濃度がminnimum inhibitory concentration以下になっても殺菌活性が残存。殺菌活性の残存時間は濃度依存的

抗菌スペクトル

広い

副作用

腎障害：近位尿細管の壊死変性。用量依存的
耳毒性：CN VIII障害。内耳の有毛細胞を破壊。用量依存的
神経・筋遮断作用：(稀であるが)神経筋遮断作用(およびこれによる無呼吸)を呈する。遮断作用はネオマイシンが一番強く、カナマイシン、アミカシン、ゲンタマイシン、トブラマイシンがこれに続く。通常、胸腔内、腹腔に大量投与した時に生じるが、静脈内、筋肉内、あるいは経口投与でも起こりうる。大抵の発作(神経筋接合部が遮断される発作)は麻酔薬やその他の神経筋接合部遮断薬の投与で生じる(←どういう意味？)。重症筋無力症の患者はアミノグリコシド系抗菌薬による神経筋接合部遮断作用を受けやすい。(GOO.1164)