Identification

Name
Vaborbactam
Accession Number
DB12107
Type
Small Molecule
Groups
Approved, Investigational
Description

Vaborbactam is a β-lactamase inhibitor based on a cyclic boronic acid pharmacophore [2]. It has been used in trials investigating the treatment of bacterial infections in subjects with varying degrees of renal insufficiency. In August 2017, a combination antibacterial therapy under the market name Vabomere was approved by the FDA for the treatment of adult patients with complicated urinary tract infections (cUTI). Vabomere consists of vaborbactam and Meropenem for intravenous administration. Vaborbactam is added to the therapy to reduce the extent of Meropenem degradation by inhibiting the serine beta-lactamases expressed by the microorganism of target [Label]. The treatment aims to resolve infection-related symptoms of cUTI and achieve negative urine culture, when the infections are proven or strongly suspected to be caused by susceptible bacteria.

Structure
Thumb
Synonyms
Not Available
External IDs
RPX-7009 / RPX7009
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
VabomereVaborbactam (1 g/2g) + Meropenem (1 g/2g)Injection, powder, for solutionIntravenousThe Medicines Company2017-10-02Not applicableUs
VabomereVaborbactam (1 g/2g) + Meropenem (1 g/2g)Injection, powder, for solutionIntravenousMelinta Therapeutics, Inc.2017-10-02Not applicableUs
Categories
UNII
1C75676F8V
CAS number
1360457-46-0
Weight
Average: 297.13
Monoisotopic: 297.084224
Chemical Formula
C12H16BNO5S
InChI Key
IOOWNWLVCOUUEX-WPRPVWTQSA-N
InChI
InChI=1S/C12H16BNO5S/c15-11(7-9-2-1-5-20-9)14-10-4-3-8(6-12(16)17)19-13(10)18/h1-2,5,8,10,18H,3-4,6-7H2,(H,14,15)(H,16,17)/t8-,10-/m0/s1
IUPAC Name
2-[(3R,6S)-2-hydroxy-3-[2-(thiophen-2-yl)acetamido]-1,2-oxaborinan-6-yl]acetic acid
SMILES
OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1

Pharmacology

Indication

Indicated in combination with meropenem for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex [Label].

Associated Conditions
Pharmacodynamics

Vaborbactam shows no antibacterial activity alone; it serves to restore the antibacterial activity of other antibacterial agents such as meropenem by attenuating their degradation by inhibiting certain serine beta-lactamases of microorganisms [Label]. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms [Label]. Vaborbactam in combination with meropenem, which is a penem antibacterial drug, potentiates the bactericidal actions of meropenem against carbapenem-resistant KPC-containing Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae in a concentration-dependent manner [3]. It restored the antimicrobial activity of meropenem in animal models of infection caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae [Label].

Mechanism of action

Vaborbactam is a cyclic boronic acid pharmacophore β-lactamase inhibitor that elicits potent inhibition of Klebsiella pneumoniae carbapenemase (KPC) enzymes and other Ambler class A and C enzymes such as serine β-lactamases that confer resistance to commonly-used antibiotics such as Carbapenems [1]. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases [2]. Vaborbactam interacts with β-lactamases of Ambler classes A and C via precovalent and covalent binding [1]. It exerts no inhibitory actions on class D or class B carbapenemases [2]. The production of contemporary β-lactamase by bacterial isolates potentiate the degradation of β-lactam antibiotic agents, rendering them clinically ineffective and posing challenges for patients receiving the standard antibiotic therapy. In combination with meropenem, varborbactam acts as a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation mediated by serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC) [3].

TargetActionsOrganism
ABeta-lactamase
inhibitor
Enterobacter cloacae
ACarbapenem-hydrolyzing beta-lactamase KPC
inhibitor
Klebsiella pneumoniae
ABeta-lactamase (KPC-2)
inhibitor
Klebsiella pneumoniae
ABeta-lactamase CTX-M
inhibitor
Escherichia coli
ABeta-lactamase (blaSHV)
inhibitor
Escherichia coli
ABeta-lactamase SHV-1
inhibitor
Klebsiella pneumoniae
ABeta-lactamase TEM
inhibitor
Escherichia coli
ABeta-lactamase AmpC
inhibitor
Enterobacter cloacae
ABeta-lactamase (MIR-1)
inhibitor
Klebsiella pneumoniae
ABeta-lactamase
inhibitor
Klebsiella pneumoniae
Absorption

The peak plasma concentrations (Cmax) and AUC of vaborbactam increase in a dose-proportional manner. In healthy adult subjects, the Cmax following administration of multiple 2 g dose as a 3-hour infusion was 55.6 mg/L and AUC was 588 mg•h/L. In patients with the same dosing regimen, the Cmax was 71.3 mg/L and AUC was 835 mg•h/L at steady state [Label]. The exposure of vaborbactam in terms of Cmax and AUC are not expected to change with repeated dosing, and there was no evidence of accumulation of vaborbactam in plasma in a repeated dosing study [3].

Volume of distribution

The steady-state volume of distribution of vaborbactam in patients was 18.6 L [Label].

Protein binding

The average serum protein binding of vaborbactam is approximately 33% [3].

Metabolism

Vaborbactam does not undergo metabolism [Label].

Route of elimination

Vaborbactam predominantly undergoes renal excretion, where about 75 to 95% of the dose is excreted unchanged in the urine over a 24 to 48 hour period [Label].

Half life

The half life of vaborbactam in healthy subjects following multiple 2 g dose administration as a 3-hour infusion was 1.68 hours. The half life of vaborbactam following administration of 2 g by 3 hour infusion was 2.25 hours [Label].

Clearance

The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route [Label]. The clearance of vaborbactam in healthy subjects following administration of multiple doses of 2 g as a 3-hour infusion was 10.9 L/h. The clearance of vaborbactam in patients following administration of 2 g by 3 hour infusion was 7.95 L/h [Label].

Toxicity

In case of overdose, general supportive treatments should be initiated and hemodialysis to remove varobactam may be performed [Label]. In a pharmacokinetic study, mild lethargy observed in the highest-dose group [3].

Affected organisms
  • Escherichia coli
  • Enterobacter cloacae
  • Klebsiella pneumoniae
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Vaborbactam which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Castanheira M, Rhomberg PR, Flamm RK, Jones RN: Effect of the beta-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5454-8. doi: 10.1128/AAC.00711-16. Print 2016 Sep. [PubMed:27381386]
  2. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
  3. Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN: Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the beta-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6326-32. doi: 10.1128/AAC.00568-16. Print 2016 Oct. [PubMed:27527080]
External Links
PubChem Compound
56649692
PubChem Substance
347828408
ChemSpider
35035409
ChEMBL
CHEMBL3317857
HET
4D6
Wikipedia
Vaborbactam
PDB Entries
4xux / 4xuz
FDA label
Download (191 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentBacterial Infections / Healthy Volunteers3
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentSubjects With Normal Renal Function / Subjects With Varying Degrees of Renal Insufficiency and1
1RecruitingOtherHealthy Volunteers1
1RecruitingTreatmentBacterial Infections1
3CompletedTreatmentAcute Pyelonephritis / Bacteremia / Hospital Acquired Bacterial Pneumonia / Intra Abdominal Infections Complicated / Urinary Tract Infection Complicated / Ventilator-associated Bacterial Pneumonia1
3CompletedTreatmentAcute Pyelonephritis / Urinary Tract Infection Complicated1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9694025No2011-08-082031-08-08Us
US8680136No2011-08-172031-08-17Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.155 mg/mLALOGPS
logP1.02ALOGPS
logP1.86ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)3.75ChemAxon
pKa (Strongest Basic)-2.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area95.86 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity67.14 m3·mol-1ChemAxon
Polarizability29.67 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 oxaborine derivatives. These are compounds containing a six-member aliphatic heterocycle made up of one oxygen atom, a boron atom, and three carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Metalloheterocyclic compounds
Sub Class
Oxaborine derivatives
Direct Parent
Oxaborine derivatives
Alternative Parents
Thiophenes / Heteroaromatic compounds / Boronic acid esters / Secondary carboxylic acid amides / Oxacyclic compounds / Organic metalloid salts / Monocarboxylic acids and derivatives / Carboxylic acids / Organonitrogen compounds / Organic oxides
show 3 more
Substituents
1,2-oxaborine derivative / Boronic acid ester / Thiophene / Heteroaromatic compound / Carboxamide group / Secondary carboxylic acid amide / Boronic acid derivative / Oxacycle / Organic metalloid salt / Monocarboxylic acid or derivatives
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Enterobacter cloacae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
Gene Name
ampC
Uniprot ID
P05364
Uniprot Name
Beta-lactamase
Molecular Weight
41301.33 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency.
Gene Name
bla
Uniprot ID
Q9F663
Uniprot Name
Carbapenem-hydrolyzing beta-lactamase KPC
Molecular Weight
31114.99 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
KPC-2
Uniprot ID
Q93LQ9
Uniprot Name
Beta-lactamase
Molecular Weight
31114.99 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
blaCTX-M-14
Uniprot ID
Q9L5C7
Uniprot Name
Beta-lactamase
Molecular Weight
30979.09 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
blaSHV
Uniprot ID
A8DZJ2
Uniprot Name
Beta-lactamase
Molecular Weight
30146.39 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
bla
Uniprot ID
P0AD64
Uniprot Name
Beta-lactamase SHV-1
Molecular Weight
31223.635 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Escherichia coli
Pharmacological action
Yes
Actions
Inhibitor
General Function
TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors.
Specific Function
Beta-lactamase activity
Gene Name
bla
Uniprot ID
P62593
Uniprot Name
Beta-lactamase TEM
Molecular Weight
31514.865 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Enterobacter cloacae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Beta-lactamase activity
Specific Function
Not Available
Gene Name
ampC
Uniprot ID
Q93CA2
Uniprot Name
Beta-lactamase
Molecular Weight
41341.41 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
MIR-1
Uniprot ID
Q9X757
Uniprot Name
Beta-lactamase
Molecular Weight
41171.28 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]
Kind
Protein
Organism
Klebsiella pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Beta-lactamase activity
Gene Name
fox-7
Uniprot ID
Q53IN1
Uniprot Name
Beta-lactamase
Molecular Weight
41063.395 Da
References
  1. Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN: Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov. [PubMed:28848018]

Drug created on October 20, 2016 15:22 / Updated on November 02, 2018 07:20