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Identification
NameTigecycline
Accession NumberDB00560  (APRD01307)
TypeSmall Molecule
GroupsApproved
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
Synonyms
(4S,4AS,5ar,12as)-9-(2-(tert-butylamino)acetamido)-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
Tigeciclina
Tigecycline
Tigecyclinum
External Identifiers
  • CL-329998
  • CL-331002
  • DMG-DMDOT
  • DMG-MINO
  • GAR-936
  • TBG-MINO
  • WAY-GAR-936
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Tigecyclinepowder for solution50 mgintravenousApotex Inc2014-10-23Not applicableCanada
Tygacilinjection, powder, lyophilized, for solution50 mg/5mLintravenousWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2005-06-01Not applicableUs
Tygacilpowder for solution53 mgintravenousPfizer Canada Inc2006-11-30Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII70JE2N95KR
CAS number220620-09-7
WeightAverage: 585.6487
Monoisotopic: 585.279863249
Chemical FormulaC29H39N5O8
InChI KeyInChIKey=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
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=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)N(C)C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as tetracyclines. These are polyketides having an octahydrotetracene-2-carboxamide skeleton, substituted with many hydroxy and other groups.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassTetracyclines
Sub ClassNot Available
Direct ParentTetracyclines
Alternative Parents
Substituents
  • Tetracycline
  • Tetracene
  • Naphthacene
  • Anthracene carboxylic acid or derivatives
  • Alpha-amino acid amide
  • N-arylamide
  • Tetralin
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Dialkylarylamine
  • Aryl ketone
  • Aralkylamine
  • Benzenoid
  • Vinylogous acid
  • Tertiary alcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Primary carboxylic acid amide
  • Polyol
  • Ketone
  • Carboxamide group
  • Secondary amine
  • Enol
  • Secondary aliphatic amine
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsTigecycline 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 actionTigecycline, 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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding71% 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 eliminationNot Available
Half life27-43 hours
ClearanceNot Available
ToxicitySince 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
PathwayCategorySMPDB ID
Tigecycline Action PathwayDrug actionSMP00712
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8344
Blood Brain Barrier-0.9836
Caco-2 permeable-0.5704
P-glycoprotein substrateSubstrate0.9098
P-glycoprotein inhibitor INon-inhibitor0.7651
P-glycoprotein inhibitor IINon-inhibitor0.895
Renal organic cation transporterNon-inhibitor0.9175
CYP450 2C9 substrateNon-substrate0.8283
CYP450 2D6 substrateNon-substrate0.8323
CYP450 3A4 substrateSubstrate0.717
CYP450 1A2 substrateNon-inhibitor0.8705
CYP450 2C9 inhibitorNon-inhibitor0.882
CYP450 2D6 inhibitorNon-inhibitor0.9079
CYP450 2C19 inhibitorNon-inhibitor0.8592
CYP450 3A4 inhibitorNon-inhibitor0.9271
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8863
Ames testNon AMES toxic0.729
CarcinogenicityNon-carcinogens0.8718
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6895 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9926
hERG inhibition (predictor II)Non-inhibitor0.6739
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
Powder for solutionintravenous50 mg
Injection, powder, lyophilized, for solutionintravenous50 mg/5mL
Powder for solutionintravenous53 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2079692 No2004-06-082012-10-02Canada
US7879828 No2009-02-052029-02-05Us
US8372995 No2010-10-082030-10-08Us
US8975242 No2008-10-242028-10-24Us
US9254328 No2006-03-132026-03-13Us
USRE40086 No1993-06-252013-06-25Us
USRE40183 No1996-04-092016-04-09Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.45 mg/mLALOGPS
logP0.66ALOGPS
logP-5.1ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)0.25ChemAxon
pKa (Strongest Basic)8.76ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area205.76 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity159.34 m3·mol-1ChemAxon
Polarizability61.77 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Mahdi Fawzi, Tianmin Zhu, Syed Shah, “Tigecycline compositons and methods of preparation.” U.S. Patent US20060247181, issued November 02, 2006.

US20060247181
General References
  1. Rose WE, Rybak MJ: Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006 Aug;26(8):1099-110. [PubMed:16863487 ]
  2. Kasbekar N: Tigecycline: a new glycylcycline antimicrobial agent. Am J Health Syst Pharm. 2006 Jul 1;63(13):1235-43. [PubMed:16790575 ]
External Links
ATC CodesJ01AA12
AHFS Codes
  • 08:12.24
PDB EntriesNot Available
FDA labelDownload (170 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
WarfarinThe serum concentration of Warfarin can be increased when it is combined with Tigecycline.
Food InteractionsNot Available

Targets

1. 16S rRNA
Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
yes
Actions
adduct
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
adduct
General Function:
Trna binding
Specific Function:
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.
Gene Name:
rpsI
Uniprot ID:
P0A7X3
Molecular Weight:
14856.105 Da
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
adduct
General Function:
Trna binding
Specific Function:
With S4 and S5 plays an important role in translational accuracy.Interacts with and stabilizes bases of the 16S rRNA that are involved in tRNA selection in the A site and with the mRNA backbone. Located at the interface of the 30S and 50S subunits, it traverses the body of the 30S subunit contacting proteins on the other side and probably holding the rRNA structure together. The combined cluste...
Gene Name:
rpsL
Uniprot ID:
P0A7S3
Molecular Weight:
13736.995 Da
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
adduct
General Function:
Trna binding
Specific Function:
Located at the top of the head of the 30S subunit, it contacts several helices of the 16S rRNA.In the E.coli 70S ribosome in the initiation state (PubMed:12809609) was modeled to contact the 23S rRNA (bridge B1a) and protein L5 of the 50S subunit (bridge B1b), connecting the 2 subunits; bridge B1a is broken in the model with bound EF-G, while the protein-protein contacts between S13 and L5 in B...
Gene Name:
rpsM
Uniprot ID:
P0A7S9
Molecular Weight:
13099.245 Da
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
adduct
General Function:
Structural constituent of ribosome
Specific Function:
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.
Gene Name:
rpsN
Uniprot ID:
P0AG59
Molecular Weight:
11580.36 Da
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
adduct
General Function:
Trna binding
Specific Function:
In the E.coli 70S ribosome in the initiation state (PubMed:12809609) it has been modeled to contact the 23S rRNA of the 50S subunit forming part of bridge B1a; this bridge is broken in the model with bound EF-G. The 23S rRNA contact site in bridge B1a is modeled to differ in different ribosomal states (PubMed:12859903), contacting alternately S13 or S19. In the 3.5 angstroms resolved ribosome s...
Gene Name:
rpsS
Uniprot ID:
P0A7U3
Molecular Weight:
10430.235 Da
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:16723578 ]
  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. doi: 10.1097/FTD.0b013e3181dda54f. [PubMed:20431506 ]
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Drug created on June 13, 2005 07:24 / Updated on August 24, 2016 02:00