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Taniborbactam (VNRX5133) is a novel, Phase 3-ready, reversible, selective, and injectable ß-lactamase inhibitor (BLI) that features uniquely potent and selective activity against both serine- and metallo-beta-lactamases. VNRX-5133 is under investigation in a fixed combination with the fourth generation cephalosporin, cefepime. Cefepime/VNRX-5133 may have the potential to provide a best-in-class broad-spectrum treatment option for infections due to carbapenem resistant pathogens including carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA), bioterror pathogens such as Burkholderia spp. and Salmonella spp. engineerable with serine- and metallo-beta-lactamases, and suspected polymicrobial infections caused by both gram-negative and gram-positive pathogens.
Physicochemical Properties
| Molecular Formula | C19H28BN3O5 | |
| Molecular Weight | 389.25372505188 | |
| Exact Mass | 389.212 | |
| CAS # | 1613268-23-7 | |
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| PubChem CID | 90205317 | |
| Appearance | Typically exists as solid at room temperature | |
| LogP | 0 | |
| Hydrogen Bond Donor Count | 5 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 7 | |
| Heavy Atom Count | 28 | |
| Complexity | 544 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C1C=C2C(OB(O)[C@H](NC(C[C@@H]3CC[C@@H](NCCN)CC3)=O)C2)=C(C(O)=O)C=1 |
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| InChi Key | PFZUWUXKQPRWAL-LDZOIKDWSA-N | |
| InChi Code | InChI=1S/C19H28BN3O5/c21-8-9-22-14-6-4-12(5-7-14)10-17(24)23-16-11-13-2-1-3-15(19(25)26)18(13)28-20(16)27/h1-3,12,14,16,22,27H,4-11,21H2,(H,23,24)(H,25,26)/t12?,14?,16-/m1/s1 | |
| Chemical Name |
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| Synonyms | VNRX-5133; VNRX5133; Taniborbactam; 1613267-49-4; VNRX5,133; Taniborbactam [INN]; Taniborbactam [USAN]; VNRX 5133 | |
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Target: Serine-β-lactamases (SBLs, Classes A, C, D) and Metallo-β-lactamases (MBLs, Class B) [1, 2]. Specific IC50 values against isolated enzymes: Class A SBL (TEM-116): 0.126 µM [1] Class A SBL (CTX-M-15): 0.03 µM [2] Class A SBL (SHV-5): 0.0004 µM [2] Class A SBL (KPC-2): 0.03 µM [2] Class B1 MBL (IMP-1): 2.51 µM [1] / 39.8 µM [2] Class B1 MBL (NDM-1): 0.0163 µM [1] / 0.19 µM [2] Class B1 MBL (VIM-1): 0.0079 µM [1] Class B1 MBL (VIM-2): 0.00053 µM [1] / 0.026 µM [2] Class B2 MBL (CphA): 2.51 µM [1] Class B3 MBL (L1): >10 µM [1] Class C SBL (AmpC from P. aeruginosa): 0.301 µM [1] Class C SBL (CMY-2): 0.007 µM [2] Class C SBL (p99 AmpC): 0.03 µM [2] Class D SBL (OXA-10): 0.234 µM [1] / 0.42 µM [2] Class D SBL (OXA-48): 0.537 µM [1] / 0.54 µM [2] Class D SBL (OXA-1): 0.16 µM [2] |
| ln Vitro |
In vitro activity: Taniborbactam hydrochloride (VNRX-5133 hydrochloride) has IC50s of 0.5 nM, 2 nM, 0.5 nM, 0.06 nM for KPC-2, OXA-48, VIM-4 of K.pneumoniae strain and VIM-2 of P.aeruginosa strain. Both cefepime/Taniborbactam hydrochloride (10 μg/mL) and meropenem/Taniborbactam hydrochloride combinations are highly active against all six of the NDM-1-producing clinical isolates from K.pneumoniae and E.coli, with MIC ranges of 16-0.25 and 1-0.125 μg/mL, respectively. In Vitro: Taniborbactam demonstrates broad-spectrum inhibition of both serine- and metallo-β-lactamases, with potent sub-micromolar IC50 values against major clinically relevant enzymes including TEM, CTX-M, KPC, NDM, and VIM. It shows significantly lower activity against IMP-1 MBL and does not inhibit subclass B3 MBL L1. [1]In antimicrobial susceptibility tests, Taniborbactam at a fixed concentration of 10 µg/mL significantly reduces the minimum inhibitory concentrations (MICs) of meropenem and cefepime against clinical isolates of E. coli and K. pneumoniae producing NDM-1. For six NDM-1-producing isolates, the MIC range for cefepime alone was >64 µg/mL, which was reduced to a range of 0.25-16 µg/mL in combination with Taniborbactam. Similarly, the MIC range for meropenem alone was >64 µg/mL, reduced to 0.125-1 µg/mL in combination with Taniborbactam. [1] Taniborbactam (20) potentiates the activity of piperacillin, cefepime, and meropenem against multi-drug resistant Gram-negative clinical isolates producing various β-lactamases (KPC, OXA, VIM, NDM). Compared to early analogs (1, 3, 17), it shows superior rescue of antibiotic activity, particularly against strains producing class D or class B enzymes. [2] Taniborbactam (20) rescues cefepime activity against serine-β-lactamase-producing Enterobacteriaceae. In a panel of isolates producing ESBLs, KPCs, class C, or class D enzymes, the cefepime/Taniborbactam combination resulted in MICs below the susceptible-dose dependent breakpoint of 8 µg/mL, whereas cefepime/tazobactam showed only modest activity. [2] Taniborbactam (20) rescues cefepime activity against metallo-β-lactamase-producing Gram-negative pathogens. In 14 clinical isolates expressing VIM or NDM MBLs, cefepime alone had MICs ranging from 32 to >512 µg/mL. The addition of Taniborbactam (4 µg/mL) reduced the MIC range to 0.125-4 µg/mL (MIC50 = 1 µg/mL, MIC90 = 4 µg/mL). In contrast, tazobactam and avibactam showed no such effect. [2] Taniborbactam (20) has no intrinsic antibacterial activity when tested alone against a panel of Gram-positive and Gram-negative bacteria, including wild-type and β-lactamase-producing strains, with MICs >128 µg/mL. This contrasts with meropenem and oxacillin, which showed potent activity against susceptible strains. [2] |
| ln Vivo |
A single dose of cefepime (32 mg/kg)/Taniborbactam hydrochloride (VNRX-5133 hydrochloride; 16 mg/kg; s.c.) achieves >4 log10 reduction in viable bacterial counts in the neutropenic mouse lung infection model against a CTX-M-14-producing strain of K.pneumoniae[2]. Combination of Cefepime (16 mg/kg) and Taniborbactam hydrochloride (16 mg/kg; s.c.; twice-a-day for 7 days) demonstrates >2 log10 reductions in viable bacterial counts in the kidney of the ascending urinary tract infection model against a CTX-M-15-producing strain of E.coli[2]. Taniborbactam hydrochloride has a T1/2 of 0.16 hours, a CL of 618 mL/h/kg, and a Vss of 143 mL/kg for mice. In Vivo: In a neutropenic mouse lung infection model using a CTX-M-14-producing K. pneumoniae strain, a single subcutaneous dose of cefepime/Taniborbactam (32 mg/kg and 16 mg/kg, respectively) achieved a >4 log10 reduction in viable bacterial counts in lung tissue at 24 hours. Cefepime alone at 32 mg/kg was not effective. The positive control, ceftazidime/avibactam (32:8 mg/kg), achieved a >3 log10 reduction. [2] In a mouse ascending urinary tract infection model using a CTX-M-15-producing E. coli strain, twice-daily subcutaneous doses of cefepime/Taniborbactam (16 mg/kg and 8 mg/kg, respectively) for 3 days resulted in a >2 log10 reduction in viable bacterial counts in the kidneys at day 7. [2] |
| Enzyme Assay |
Enzyme Assay: Inhibitory activity of Taniborbactam against a panel of representative serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs) was determined using a fluorogenic assay. The assay monitored the enzymatic breakdown of the cephalosporin probe FC5, except for the subclass B2 MBL CphA, for which meropenem hydrolysis was used. The assays were conducted at room temperature in microplates. SBLs (TEM-116, AmpC, OXA-10, OXA-48) were tested in a phosphate buffer (pH 7.4) with 0.01% Triton X-100. OXA-10 and OXA-48 assays were also supplemented with 100 mM NaHCO3. MBLs (IMP-1, VIM-1, VIM-2, NDM-1, L1, CphA) were screened in HEPES buffer (50 mM, pH 7.2) containing 1 µM ZnSO4, 1 µg/mL BSA, and 0.01% Triton X-100. The enzymes were tested at specific concentrations (e.g., AmpC at 500 pM, NDM-1 at 20 pM). The probe FC5 was used at 5 or 10 µM, and meropenem at 12.5 µM for CphA. The initial rates of reaction were assessed after a 10-minute pre-incubation of Taniborbactam with the enzyme, by monitoring fluorescence intensity (λex=380 nm, λem=460 nm) or UV absorbance (λ=300 nm for CphA). Data were fitted using a four-parameter function in GraphPad Prism 6 to obtain IC50 values. Varying pre-incubation times of Taniborbactam with NDM-1 did not result in different IC50 values, supporting reversible inhibition. [1] Inhibition assays for compound 20 were performed against a panel of β-lactamases from classes A to D. The exact methodology is not detailed in this section, but results are presented as IC50 values (µM) for enzymes including SHV-5, CTX-M-15, KPC-2, CMY-2, p99 AmpC, OXA-1, OXA-48, NDM-1, VIM-2, and IMP-1. [2] |
| Cell Assay |
Cell Assay: Antimicrobial susceptibility was tested using the agar dilution method. Minimum inhibitory concentration (MIC) values were determined for meropenem and cefepime alone (0.06-64 µg/mL) and in combination with a fixed concentration (10 µg/mL) of Taniborbactam against a panel of six NDM-1-producing clinical isolates of E. coli and K. pneumoniae. MICs were interpreted using EUCAST/CLSI guidelines. All reported MIC values were within ±1 log2 dilution of the reference MIC values. [1] The ability of Taniborbactam to potentiate β-lactam antibiotics (piperacillin, cefepime, meropenem) was evaluated against MDR Gram-negative clinical isolates. MICs for the β-lactam alone and in combination with a fixed concentration of BLI were determined. For compound 20, the MIC of the BLI required to restore meropenem activity (fixed at 4 µg/mL) was determined against K. pneumoniae (KPC-2, OXA-48, VIM-4 producers) and P. aeruginosa (VIM-2 producer). The rescue of cefepime activity by Taniborbactam (4 µg/mL) was tested against Enterobacteriaceae expressing ESBLs, KPCs, class C, or class D enzymes, and against 14 MBL-producing Gram-negative pathogens (including E. coli, E. cloacae, K. pneumoniae, P. aeruginosa, A. baumannii) expressing VIM or NDM. MIC testing was conducted using CLSI broth microdilution assays. [2] The intrinsic antibacterial activity of Taniborbactam was tested against a panel of Gram-positive (S. aureus) and Gram-negative (E. coli, K. pneumoniae, E. cloacae, E. aerogenes, P. aeruginosa) strains, including wild-type and β-lactamase-producing variants. MICs were determined following CLSI guidelines. [2] |
| Animal Protocol |
Animal Protocol: Pharmacokinetic (PK) studies of Taniborbactam (20), cefepime, and avibactam were performed in mice following intravenous administration. The specific formulation, dosing frequency, and route (IV) are mentioned, but detailed protocols like vehicle composition are not described. [2] Neutropenic Mouse Lung Infection Model: Female CD-1 mice were rendered neutropenic. They were infected intranasally with a CTX-M-14-producing K. pneumoniae strain. Two hours post-infection, a single subcutaneous dose of cefepime (32 mg/kg) alone, cefepime/Taniborbactam (32:16 mg/kg), or ceftazidime/avibactam (32:8 mg/kg) was administered. At 24 hours post-infection, mice were euthanized, and lungs were harvested for bacterial colony-forming unit (CFU) enumeration. [2] Mouse Ascending Urinary Tract Infection Model: Female BALB/c mice were infected transurethrally with a CTX-M-15-producing E. coli strain. Treatment began 24 hours post-infection and was administered subcutaneously twice daily for 3 days. Groups received cefepime (16 mg/kg) alone, cefepime/Taniborbactam (16:8 mg/kg), or ceftazidime/avibactam (16:4 mg/kg). On day 7 post-infection, mice were euthanized, and kidneys were harvested for CFU enumeration. [2] |
| ADME/Pharmacokinetics | ADME/Pharmacokinetics: In mice following intravenous administration, Taniborbactam (20) exhibited a PK profile typical of highly polar, ionizable compounds, similar to β-lactams. The parameters were: t1/2 = 0.16 h, AUCint = 16,189 h·ng/mL, Vss = 436 mL/kg, and CL = 1,818 mL/h/kg. Compared to avibactam, Taniborbactam showed higher exposure (AUC) and lower clearance (CL). [2] |
| Toxicity/Toxicokinetics |
Taniborbactam (20) displayed no cytotoxicity (<20% inhibition of growth) when tested up to 256 µg/mL against HeLa, MRC-5, and 3T3 mammalian cell lines. No toxicity was observed in human primary renal proximal tubule cells when tested up to 1000 µg/mL. [2] Taniborbactam (20) had no significant activity when tested at 100 µM against a panel of 50 human enzymes and receptors. This panel included serine proteases (cathepsin G, chymotrypsin, Factor Xa, trypsin, neutrophil elastase 2), metalloproteinases (MMP-1, -2, -3, -9), cytochrome P450s (1A2, 2C9, 2C19, 2D6, 3A4), and the hERG potassium channel. [2] |
| References |
[1]. Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases. J Med Chem. 2019 Sep 26;62(18):8544-8556. [2]. Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. J Med Chem. 2020 Mar 26;63(6):2789-2801. |
| Additional Infomation |
Taniborbactam (formerly VNRX-5133) is a bicyclic boronate β-lactamase inhibitor in clinical development (Phase 3 trials as of the publication). It is designed as a broad-spectrum inhibitor to combat antibiotic resistance in Gram-negative bacteria. [1, 2] The mechanism of action involves mimicking the tetrahedral intermediate in β-lactam hydrolysis. It inhibits serine-β-lactamases (SBLs) by forming a covalent adduct with the active-site serine and inhibits metallo-β-lactamases (MBLs) by interacting with the active-site zinc ions, acting as a "high-energy-intermediate" analogue. [1, 2] Crystallographic studies reveal that Taniborbactam binds to SBLs (e.g., OXA-10, CTX-M-15) via a covalent bond to the catalytic serine. In MBLs (e.g., NDM-1, VIM-2), the tetrahedral boron interacts with the zinc ions. An unexpected tricyclic binding form was observed in the NDM-1 active site, suggesting the boron atom can undergo further reactions. The conserved binding of the bicyclic core across enzyme classes and differing side-chain orientations imply further optimization is possible. [1, 2] Taniborbactam is being developed in combination with the fourth-generation cephalosporin, cefepime, to treat serious Gram-negative bacterial infections, including those caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. This combination avoids the use of carbapenems, potentially reducing resistance-selective pressure. A Phase 3 efficacy trial for cefepime/Taniborbactam (NCT03840148) was in progress at the time of the second publication. [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5690 mL | 12.8452 mL | 25.6904 mL | |
| 5 mM | 0.5138 mL | 2.5690 mL | 5.1381 mL | |
| 10 mM | 0.2569 mL | 1.2845 mL | 2.5690 mL |