Identification

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Name
Omadacycline
Accession Number
DB12455
Type
Small Molecule
Groups
Approved, Investigational
Description

Omadacycline has been used in trials studying the treatment of Bacterial Pneumonia, Bacterial Infections, Community-Acquired Infections, and Skin Structures and Soft Tissue Infections. Omadacycline represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings.

Structure
Thumb
Synonyms
  • Amadacycline
  • Omadacycline
External IDs
BAY 73-6944
Product Ingredients
IngredientUNIICASInChI Key
Omadacycline tosylate5658Y89YCD1075240-43-5SETFNHZTVGTBHC-XGLFQKEBSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NuzyraTablet, film coated150 mg/1OralParatek Pharmaceuticals, Inc.2019-02-01Not applicableUs
NuzyraInjection, powder, lyophilized, for solution100 mg/5mLIntravenousParatek Pharmaceuticals, Inc.2019-02-01Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
090IP5RV8F
CAS number
389139-89-3
Weight
Average: 556.66
Monoisotopic: 556.289699644
Chemical Formula
C29H40N4O7
InChI Key
JEECQCWWSTZDCK-IQZGDKDPSA-N
InChI
InChI=1S/C29H40N4O7/c1-28(2,3)12-31-11-14-10-17(32(4)5)15-8-13-9-16-21(33(6)7)24(36)20(27(30)39)26(38)29(16,40)25(37)18(13)23(35)19(15)22(14)34/h10,13,16,21,31,34,36-37,40H,8-9,11-12H2,1-7H3,(H2,30,39)/t13-,16-,21-,29-/m0/s1
IUPAC Name
(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-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(CNCC(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

Pharmacology

Indication

Omadacycline is indicated for the treatment of community acquired bacterial pneumonia and acute bacterial skin and skin structure infections caused by omadacycline-susceptible organisms in adults.Label

Associated Conditions
Pharmacodynamics

Omadacycline can be either bacteriostatic or bacteriocidal depending on the organism involved.1,3 It disrupts bacterial protein synthesis without affecting DNA, RNA, or peptidoglycan synthesis. Omadacycline represents an improvement over existing tetracycline agents as it has not been found to be subject to tetracycline resistance mediated by tetracycline efflux pumps encoded by the tet(K), tet(L), and tet(B) or to ribosomal protection proteins encoded by tet(O) and tet(M).Label,1,2 Omadacycline is susceptible to RNA mutations which confer resistance to tetracyclines.4

Mechanism of action

Omadacycline binds to the primary tetracycline binding site on the bacterial 30s ribosomal subunit with high specificity.4 There it acts to block protein synthesis, disrupting many facets of cellular function and resulting in either cell death or stasis.1,2,3

TargetActionsOrganism
A30S ribosomal protein S3
inhibitor
Escherichia coli (strain K12)
A30S ribosomal protein S7
inhibitor
Escherichia coli (strain K12)
A30S ribosomal protein S8
inhibitor
Escherichia coli (strain K12)
A30S ribosomal protein S19
inhibitor
Escherichia coli (strain K12)
A30S ribosomal protein S14
inhibitor
Escherichia coli (strain K12)
A16S rRNA
inhibitor
Enteric bacteria and other eubacteria
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

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Additional Data Available
Blackbox Warnings

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Absorption

Omadacycline has an mean absolute oral bioavailability of 34.5% and a mean Tmax of2.5 h with oral dosing. With multiple dosing, Omadacycline displays an accumulation factor of 1.5. Label Official labeling states that food does not significantly impact rate or extent of absorption, however, conflicting data exists suggesting food may lower the bioavailability of omadacycline taken after eating. Label,5 The exposure in alveolar cells and epithelial lining fluid is 25.8 and 1.5 fold higher than plasma exposure after IV administration, suggesting Omadacycline penetrates the lungs to a significant degree.Label

Volume of distribution

Omadacycline has a mean Vd of 256 L after a single dose and a Vss of 190 L.Label

Protein binding

Omadacycline exhibits non-linear protein binding and remains 20% bound independent of concentration.Label

Metabolism

Omadacycline is not known to be metabolized in humans.Label

Route of elimination

After IV dosing 27% of Omadacycline was eliminated by the kidneys. In oral dosing 14.4% was found to be eliminated by the kidneys and 81.1% in the feces.Label Neither renal nor hepatic impairment appears to produce a clinically relevant effect elimination.

Half life

Omadacycline has a mean half life of elimination of 16.2 h. Label

Clearance

Omadacycline has a mean systemic clearance of 11.24 L/h and a renal clearance of 2.4-3.3 L/h.Label

Toxicity

No carcinogenicity studies have been conducted with Omadacycline, however, other tetracycline drugs have shown oncogenicity.Label Specifically, oxytetracycline increased incidence of adrenal and pituitary tumors and minocycline increased incidence of thyroid tumors.

Omadacycline has tested positive for clastogenicity and aneugenicity during in-vitro Chinese hamster ovary cell studies and for mutagenicity in mouse lymphoma cells.Label Both positive results occurred in the presence of metabolizing enzymes. Omadacycline has tested negative for chromosomal aberration of any kind during in-vitro Chinese hamster V79 cell testing. It has further tested negative during in-vivo micronucleus assays in ICR mice and HanRcc: WIST rats.

Omadacycline reduced sperm counts and sperm-motility in male rats at repeat dosages equivalent to 1.3 times the normal human exposure but produced no effect on fertility parameters.Label Inhibition of spermatogenesis was noted at repeat dosages equivalent to 6-8 times normal human exposure for a duration greater than 37 days but not at dosages under 2 times normal human exposure or durations of less than 4 weeks. Ovulation and embryonic survival was reduced in female rats at dosages approximating normal human exposure administered before mating through early pregnancy.

Thyroid hyperpigmentation, goitrogenicity, thyroid hyperplasia, and adrenal have been noted in multiple animal studies using other tetracycline drugs.Label

Affected organisms
  • Streptococcus pyogenes
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Mycoplasma pneumoniae
  • Legionella pneumophila
  • Staphylococcus aureus
  • Enterococcus faecalis
  • Staphylococcus lugdunensis
  • Streptococcus anginosus
  • Streptococcus constellatus
  • Enterobacter cloacae
  • Klebsiella pneumoniae
  • Haemophilus parainfluenzae
  • Streptococcus intermedius
  • Chlamydophila pneumoniae
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Omadacycline is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Omadacycline is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Omadacycline is combined with 4-hydroxycoumarin.
4-OxoretinolThe risk or severity of pseudotumor cerebri and elevated intracranial pressure can be increased when 4-Oxoretinol is combined with Omadacycline.
AbemaciclibThe serum concentration of Omadacycline can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Omadacycline can be increased when it is combined with Acebutolol.
AcenocoumarolThe risk or severity of bleeding can be increased when Omadacycline is combined with Acenocoumarol.
AcetaminophenThe serum concentration of Omadacycline can be increased when it is combined with Acetaminophen.
Acetylcysteine zincAcetylcysteine zinc can cause a decrease in the absorption of Omadacycline resulting in a reduced serum concentration and potentially a decrease in efficacy.
AcetyldigoxinOmadacycline can cause an increase in the absorption of Acetyldigoxin resulting in an increased serum concentration and potentially a worsening of adverse effects.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
  2. Draper MP, Weir S, Macone A, Donatelli J, Trieber CA, Tanaka SK, Levy SB: Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother. 2014;58(3):1279-83. doi: 10.1128/AAC.01066-13. Epub 2013 Sep 16. [PubMed:24041885]
  3. Tanaka SK, Steenbergen J, Villano S: Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. Bioorg Med Chem. 2016 Dec 15;24(24):6409-6419. doi: 10.1016/j.bmc.2016.07.029. Epub 2016 Jul 18. [PubMed:27469981]
  4. Heidrich CG, Mitova S, Schedlbauer A, Connell SR, Fucini P, Steenbergen JN, Berens C: The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome. Antibiotics (Basel). 2016 Sep 22;5(4). pii: antibiotics5040032. doi: 10.3390/antibiotics5040032. [PubMed:27669321]
  5. Tzanis E, Manley A, Villano S, Tanaka SK, Bai S, Loh E: Effect of Food on the Bioavailability of Omadacycline in Healthy Participants. J Clin Pharmacol. 2017 Mar;57(3):321-327. doi: 10.1002/jcph.814. Epub 2016 Sep 22. [PubMed:27539539]
External Links
PubChem Compound
54697325
PubChem Substance
347828696
ChemSpider
20131003
ChEMBL
CHEMBL1689772
Wikipedia
Omadacycline
ATC Codes
J01AA20 — Combinations of tetracyclines
FDA label
Download (2.6 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentCystitis / Uncomplicated Urinary Tract Infections1
2RecruitingTreatmentAcute Pyelonephritis1
3CompletedTreatmentBacterial Infections / Skin Structures and Soft Tissue Infections2
3CompletedTreatmentCommunity-Acquired Infections / Pneumonia, Bacterial1
3TerminatedTreatmentSkin Diseases, Infectious1
3WithdrawnTreatmentSkin Structures and Soft Tissue Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous100 mg/5mL
Tablet, film coatedOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US10111890No2018-10-302037-08-03Us
US10124014No2018-11-132029-03-05Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.213 mg/mLALOGPS
logP0.94ALOGPS
logP-2.2ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)2.87ChemAxon
pKa (Strongest Basic)10.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area176.66 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity153.93 m3·mol-1ChemAxon
Polarizability60.02 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Tetracyclines
Sub Class
Not Available
Direct Parent
Tetracyclines
Alternative Parents
Naphthacenes / Anthracenecarboxylic acids and derivatives / Tetralins / Aryl ketones / Dialkylarylamines / Aralkylamines / Cyclohexenones / Phenols / Tertiary alcohols / Vinylogous acids
show 8 more
Substituents
Tetracycline / Naphthacene / Tetracene / Anthracene carboxylic acid or derivatives / Tetralin / Dialkylarylamine / Aryl ketone / Tertiary aliphatic/aromatic amine / Cyclohexenone / Phenol
show 25 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Structural constituent of ribosome
Specific Function
Binds the lower part of the 30S subunit head. Binds mRNA in the 70S ribosome, positioning it for translation (By similarity).Plays a role in mRNA unwinding by the ribosome, possibly by forming part...
Gene Name
rpsC
Uniprot ID
P0A7V3
Uniprot Name
30S ribosomal protein S3
Molecular Weight
25983.07 Da
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Trna binding
Specific Function
One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it nucleates assembly of the head domain of the 30S subunit. Is located at the subunit interface close to the decoding ...
Gene Name
rpsG
Uniprot ID
P02359
Uniprot Name
30S ribosomal protein S7
Molecular Weight
20018.91 Da
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Structural constituent of ribosome
Specific Function
One of the primary rRNA binding proteins, it binds directly to 16S rRNA central domain where it helps coordinate assembly of the platform of the 30S subunit.Protein S8 is a translational repressor ...
Gene Name
rpsH
Uniprot ID
P0A7W7
Uniprot Name
30S ribosomal protein S8
Molecular Weight
14126.435 Da
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
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 wi...
Gene Name
rpsS
Uniprot ID
P0A7U3
Uniprot Name
30S ribosomal protein S19
Molecular Weight
10430.235 Da
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
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
Uniprot Name
30S ribosomal protein S14
Molecular Weight
11580.36 Da
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]
6. 16S rRNA
Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
Yes
Actions
Inhibitor
References
  1. Anokhina MM, Barta A, Nierhaus KH, Spiridonova VA, Kopylov AM: Mapping of the second tetracycline binding site on the ribosomal small subunit of E.coli. Nucleic Acids Res. 2004 May 11;32(8):2594-7. doi: 10.1093/nar/gkh583. Print 2004. [PubMed:15141029]
  2. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR: Omadacycline Enters the Ring: A New Antimicrobial Contender. Pharmacotherapy. 2018 Oct 5. doi: 10.1002/phar.2185. [PubMed:30290000]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 20, 2016 16:27 / Updated on June 04, 2019 07:38