DrugBank: Tigecycline (DB00560)

targets (6)

Identification

Name

Tigecycline

Accession Number

DB00560 (APRD01307)

Type

small molecule

Groups

approved

Description

Tigecycline is a glycylcycline antibiotic developed and marketed by Wyeth under the brand name Tygacil. It was given a U.S. Food and Drug Administration (FDA) fast-track approval and was approved on June 17, 2005. It was developed in response to the growing prevalence of antibiotic resistance in bacteria such as Staphylococcus aureus.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

GAR-936
GAR-936,Tigecycline
WAY-GAR-936

Brand names

Tygacil

Brand name mixtures

Not Available

Categories

Anti-Bacterial Agents
Tetracyclines
Antibacterial Agents

CAS number

220620-09-7

Weight

Average: 585.6487
Monoisotopic: 585.279863249

Chemical Formula

C₂₉H₃₉N₅O₈

InChI Key

InChIKey=FPZLLRFZJZRHSY-HJYUBDRYSA-N

InChI

InChI=1S/C29H39N5O8/c1-28(2,3)31-11-17(35)32-15-10-16(33(4)5)13-8-12-9-14-21(34(6)7)24(38)20(27(30)41)26(40)29(14,42)25(39)18(12)23(37)19(13)22(15)36/h10,12,14,21,31,36,38-39,42H,8-9,11H2,1-7H3,(H2,30,41)(H,32,35)/t12-,14-,21-,29-/m0/s1

Plain Text

IUPAC Name

(4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

SMILES

[H][C@@]12CC3=C(C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)C(O)=C(NC(=O)CNC(C)(C)C)C=C3N(C)C

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Tetracyclines

Substructures

Tetracyclines
Hydroxy Compounds
Benzyl Alcohols and Derivatives
Naphthalenes
Aliphatic and Aryl Amines
Phenols and Derivatives
Amino Ketones
Phenylpropenes
Benzene and Derivatives
Carboxylic Acids and Derivatives
Aminophenols and Derivatives
Alcohols and Polyols
Aromatic compounds
Cinnamaldehydes
Carboxamides and Derivatives
Ketenes and Derivatives
Phenyl Esters
Anilines
Enols
Ketones

Pharmacology

Indication

For the treatment of infections caused by susceptible strains of the designated microorganisms in the following conditions: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes and Bacteroides fragilis. Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Pharmacodynamics

Tigecycline is the first clinically-available drug in a new class of antibiotics called the glycylcyclines. Glycylcyclines are a new class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. Glycylcycline antibiotics have a similar mechanism of action as tetracycline antibiotics. Both classes of antibiotics bind to the 30S ribosomal subunit to prevent the amino-acyl tRNA from binding to the A site of the ribosome. However, the glycylcyclines appear to bind more effectively than the tetracyclines.

Mechanism of action

Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. Tigecycline is not affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. Tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerase). In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterial drugs. In general, tigecycline is considered bacteriostatic.

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

71% to 89%

Metabolism

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. A glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) are the primary metabolites.

Route of elimination

Not Available

Half life

27-43 hours

Clearance

Not Available

Toxicity

Since glycylcyclines are similar to tetracyclines, they share many of the same side effects and contraindications as tetracyclines. These side effects may include nausea/vomiting, headache, photosensitivity, discoloration of growing teeth, and fetal damage.

Affected organisms

Enteric bacteria and other eubacteria

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Wyeth pharmaceuticals inc

Packagers

Dosage forms

Form	Route	Strength
Powder, for solution	Intravenous

Prices

Not Available

Patents

Country	Patent Number	Approved	Expires
United States	RE40183	1996-04-09	2016-04-09
United States	RE40086	1993-06-25	2013-06-25
Canada	2079692	2004-06-08	2012-10-02

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
logP	0.8	PhysProp

Predicted Properties

Property	Value	Source
water solubility	4.50e-01 g/l	ALOGPS
logP	0.66	ALOGPS
logP	-5.47	ChemAxon Molconvert
logS	-3.11	ALOGPS
pKa	4.37	ChemAxon Molconvert
hydrogen acceptor count	11	ChemAxon Molconvert
hydrogen donor count	7	ChemAxon Molconvert
polar surface area	205.76	ChemAxon Molconvert
rotatable bond count	7	ChemAxon Molconvert
refractivity	159.34	ChemAxon Molconvert
polarizability	61.77	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Rose WE, Rybak MJ: Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006 Aug;26(8):1099-110. Pubmed
Kasbekar N: Tigecycline: a new glycylcycline antimicrobial agent. Am J Health Syst Pharm. 2006 Jul 1;63(13):1235-43. Pubmed

External Links

Resource	Link
KEGG Drug	D01079
KEGG Compound	C12012
PubChem Compound	5282044
PubChem Substance	46509041
ChemSpider	4445273
ChEBI	149836
ChEMBL	149836
Therapeutic Targets Database	DAP000880
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic4/tygacil.htm
Drugs.com	http://www.drugs.com/cdi/tigecycline.html
Wikipedia	http://en.wikipedia.org/wiki/Tigecycline

ATC Codes

J01AA12

AHFS Codes

08:12.24

PDB Entries

Not Available

FDA label

show (170.3 KB)

MSDS

Not Available

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. 16S rRNA Pharmacological action: yes Actions: adduct In prokaryotes, the 16S rRNA is essential for recognizing the 5' end of mRNA and hence positioning it correctly on the ribosome. The 16S rRNA has a characteristic secondary structure in which half of the nucleotides are base-paired. The 16S rRNA sequence has been highly conserved and is often used for evolutionary and species comparative analysis. Gene Sequence: FASTA References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed 2. 30S ribosomal protein S9 Pharmacological action: yes Actions: adduct The C-terminal tail plays a role in the affinity of the 30S P site for different tRNAs. Mutations that decrease this affinity are suppressed in the 70S ribosome Organism class: bacterial UniProt ID: P0A7X3 Gene: rpsI Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed 3. 30S ribosomal protein S12 Pharmacological action: yes Actions: adduct Cryo-EM studies suggest that S12 contacts the EF-Tu bound tRNA in the A-site during codon-recognition. This contact is most likely broken as the aminoacyl-tRNA moves into the peptidyl transferase center in the 50S subunit Organism class: bacterial UniProt ID: P0A7S3 Gene: rpsL Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed 4. 30S ribosomal protein S13 Pharmacological action: yes Actions: adduct The C-terminal tail plays a role in the affinity of the 30S P site for different tRNAs Organism class: bacterial UniProt ID: P0A7S9 Gene: rpsM Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed 5. 30S ribosomal protein S14 Pharmacological action: yes Actions: adduct Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site Organism class: bacterial UniProt ID: P0AG59 Gene: rpsN Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed 6. 30S ribosomal protein S19 Pharmacological action: yes Actions: adduct Protein S19 forms a complex with S13 that binds strongly to the 16S ribosomal RNA. Contacts the A site tRNA Organism class: bacterial UniProt ID: P0A7U3 Gene: rpsS Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

Targets

1. 16S rRNA

Pharmacological action: yes
Actions: adduct

In prokaryotes, the 16S rRNA is essential for recognizing the 5' end of mRNA and hence positioning it correctly on the ribosome. The 16S rRNA has a characteristic secondary structure in which half of the nucleotides are base-paired. The 16S rRNA sequence has been highly conserved and is often used for evolutionary and species comparative analysis.

Gene Sequence: FASTA

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

2. 30S ribosomal protein S9

Pharmacological action: yes
Actions: adduct

The C-terminal tail plays a role in the affinity of the 30S P site for different tRNAs. Mutations that decrease this affinity are suppressed in the 70S ribosome

Organism class: bacterial
UniProt ID: P0A7X3 Link_out

Gene: rpsI
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

3. 30S ribosomal protein S12

Pharmacological action: yes
Actions: adduct

Cryo-EM studies suggest that S12 contacts the EF-Tu bound tRNA in the A-site during codon-recognition. This contact is most likely broken as the aminoacyl-tRNA moves into the peptidyl transferase center in the 50S subunit

Organism class: bacterial
UniProt ID: P0A7S3 Link_out

Gene: rpsL
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

4. 30S ribosomal protein S13

Pharmacological action: yes
Actions: adduct

The C-terminal tail plays a role in the affinity of the 30S P site for different tRNAs

Organism class: bacterial
UniProt ID: P0A7S9 Link_out

Gene: rpsM Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

5. 30S ribosomal protein S14

Pharmacological action: yes
Actions: adduct

Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site

Organism class: bacterial
UniProt ID: P0AG59 Link_out

Gene: rpsN Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

6. 30S ribosomal protein S19

Pharmacological action: yes
Actions: adduct

Protein S19 forms a complex with S13 that binds strongly to the 16S ribosomal RNA. Contacts the A site tRNA

Organism class: bacterial
UniProt ID: P0A7U3 Link_out

Gene: rpsS Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O’Connell J, Bradford PA: Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66. Pubmed
da Silva LM, Nunes Salgado HR: Tigecycline: a review of properties, applications, and analytical methods. Ther Drug Monit. 2010 Jun;32(3):282-8. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:04

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.