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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 Thumb
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
  1. Rose WE, Rybak MJ: Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006 Aug;26(8):1099-110. Pubmed
  2. 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 Link_out
KEGG Compound C12012 Link_out
PubChem Compound 5282044 Link_out
PubChem Substance 46509041 Link_out
ChemSpider 4445273 Link_out
ChEBI 149836 Link_out
ChEMBL 149836 Link_out
Therapeutic Targets Database DAP000880 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic4/tygacil.htm Link_out
Drugs.com http://www.drugs.com/cdi/tigecycline.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tigecycline Link_out
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:
  1. 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
  2. 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:
  1. 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
  2. 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:
  1. 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
  2. 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:
  1. 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
  2. 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:
  1. 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
  2. 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:
  1. 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
  2. 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.