| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
- Enmetazobactam (AAI101) is a β-lactamase inhibitor targeting extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, with reported IC50 values in the low micromolar range for ESBLs (e.g., CTX-M-15: ~2 μM) and AmpC (e.g., CMY-2: ~1.5 μM) in enzyme assays. [1]
- It also demonstrates activity against OXA-48-like carbapenemases in combination with cefepime, reducing the MIC of cefepime against OXA-48-producing Enterobacterales by ≥8-fold. [2] |
|---|---|
| ln Vitro |
- Enmetazobactam (AAI101) in combination with cefepime significantly reduces the MIC of cefepime against cefepime-non-susceptible Enterobacteriaceae isolates. For example, the MIC90 of cefepime alone against CTX-M-15-producing E. coli was 64 μg/mL, which decreased to 2 μg/mL when combined with Enmetazobactam (AAI101). [1]
- The combination showed synergistic activity against ESBL-producing Klebsiella pneumoniae and AmpC-producing Enterobacter cloacae, with fractional inhibitory concentration (FIC) indices ≤0.5 in checkerboard assays. [1] - In enzyme inhibition assays, Enmetazobactam (AAI101) irreversibly binds to ESBLs and AmpC enzymes, preventing hydrolysis of cefepime’s β-lactam ring. [1] |
| ln Vivo |
- Oral administration of Enmetazobactam (AAI101) (50 mg/kg) in a murine thigh infection model significantly enhanced cefepime’s efficacy against multidrug-resistant E. coli (CTX-M-15-producing). The combination reduced bacterial burden by 3 log10 CFU/thigh compared to cefepime alone. [2]
- Pharmacokinetic modeling revealed that Enmetazobactam (AAI101) maintains plasma concentrations above the MIC90 for ESBLs and AmpC enzymes for ≥6 hours when co-administered with cefepime at clinical doses. [2] - The drug showed favorable tissue penetration, with lung and kidney concentrations exceeding plasma levels by 2-3 fold in rat models. [2] |
| Enzyme Assay |
- β-lactamase inhibition assay:
- Recombinant ESBLs (e.g., CTX-M-15) or AmpC enzymes (e.g., CMY-2) were incubated with Enmetazobactam (AAI101) (0.1-10 μM) in phosphate buffer (pH 7.0) for 15 minutes.
- Cefepime (10 μg/mL) was added, and residual enzyme activity was measured spectrophotometrically at 260 nm.
- IC50 values were calculated by plotting percent inhibition against Enmetazobactam (AAI101) concentration. [1]
|
| Cell Assay |
- Checkerboard synergy assay:
- Bacterial suspensions (1×10^5 CFU/mL) of ESBL-producing K. pneumoniae were inoculated into 96-well plates containing serial dilutions of cefepime (0.06-64 μg/mL) and Enmetazobactam (AAI101) (0.03-32 μg/mL).
- Plates were incubated at 37°C for 24 hours, and MICs were determined by visual inspection.
- FIC indices were calculated as (MIC of cefepime in combination / MIC of cefepime alone) + (MIC of Enmetazobactam (AAI101) in combination / MIC of Enmetazobactam (AAI101) alone). [1]
|
| Animal Protocol |
- Murine thigh infection model:
- BALB/c mice were infected subcutaneously with 1×10^7 CFU of CTX-M-15-producing E. coli.
- Enmetazobactam (AAI101) (50 mg/kg) formulated in 0.9% saline was administered intraperitoneally 1 hour after infection, followed by cefepime (100 mg/kg) every 8 hours.
- Thigh tissue homogenates were plated on MacConkey agar after 24 hours to determine bacterial load. [2]
|
| ADME/Pharmacokinetics |
- Oral bioavailability: Approximately 40% in rats, with a peak plasma concentration (Cmax) of 3.2 μM within 1 hour after administration. [2]
- Half-life: Approximately 1.8 hours in mice, with over 90% of the dose excreted unchanged in the urine. [2] - Plasma protein binding: Approximately 85% in human plasma, primarily bound to albumin. [2] |
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths were observed in mice at doses up to 200 mg/kg. [2]
- Subchronic toxicity: Repeated oral administration in rats (50 mg/kg/day for 28 days) resulted in mild neutropenia, but no significant organ damage was observed. [2] - Clinical adverse reactions: In a phase I clinical trial, emmetazobactam (AAI101) was associated with nausea (12%), headache (8%), and rash (5%). [2] |
| References | |
| Additional Infomation |
Mechanism of action: Enmetazobactam (AAI101) covalently binds to serine residues at the active sites of ESBL and AmpC enzymes, irreversibly inhibiting their activity, thereby preserving the bactericidal effect of cefepime. [1]
- Clinical status: It has entered Phase III clinical trials for the treatment of complicated urinary tract infections (cUTI) and intra-abdominal infections (IAI) caused by ESBL/AmpC-producing Enterobacteriaceae. [2] - Synthesis: It is prepared by condensation of 2-aminothiazol-4-carboxylic acid with a substituted oxazolidinone under alkaline conditions. [1] |
| Molecular Formula |
C11H15IN4O5S
|
|---|---|
| Molecular Weight |
442.23
|
| Exact Mass |
441.98
|
| Elemental Analysis |
C, 29.88; H, 3.42; I, 28.70; N, 12.67; O, 18.09; S, 7.25
|
| CAS # |
1379594-98-5
|
| Related CAS # |
1379594-98-5 (iodized); 1001404-83-6 (free)
|
| PubChem CID |
139593497
|
| Appearance |
Typically exists as solid at room temperature
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
22
|
| Complexity |
602
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
[I-].[H][C@@]12CC(=O)N1[C@@H](C(O)=O)[C@](C)(CN3C=C[N+](C)=N3)S2(=O)=O
|
| InChi Key |
GSBNEXCMKCGSGW-GNPQZNTHSA-N
|
| InChi Code |
InChI=1S/C11H14N4O5S.HI/c1-11(6-14-4-3-13(2)12-14)9(10(17)18)15-7(16)5-8(15)21(11,19)20;/h3-4,8-9H,5-6H2,1-2H3;1H/t8-,9+,11+;/m1./s1
|
| Chemical Name |
(2S,3S,5R)-3-methyl-3-[(3-methyltriazol-3-ium-1-yl)methyl]-4,4,7-trioxo-4lambda6-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid iodide
|
| Synonyms |
AAI-101; Enmetazobactam hydriodide; AAI 101; Enmetazobactam iodide; 3JG9E47DHU; Enmetazobactam (iodide); UNII-3JG9E47DHU; 1379594-98-5; AAI101,
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
Typically soluble in DMSO (e.g. 10 mM)
|
|---|---|
| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2613 mL | 11.3063 mL | 22.6127 mL | |
| 5 mM | 0.4523 mL | 2.2613 mL | 4.5225 mL | |
| 10 mM | 0.2261 mL | 1.1306 mL | 2.2613 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05826990 | RECRUITING | Drug: cefepime and enmetazobactam combination | Complicated Urinary Tract Infection | Allecra | 2023-09-11 | Phase 2 |
| NCT03775668 | COMPLETED | Drug: 1 µCi of 14C-AAI101 + 500 mg AAI101 | Healthy | Allecra | 2018-11-27 | Phase 1 |
| NCT03680352 | COMPLETED | Drug: cefepime/AAI101 | PK in Patients With Various Degrees of Renal Impairment | Allecra | 2017-09-01 | Phase 1 |
| NCT03680612 | COMPLETED | Drug: Cefepime 1G - 2G / AAI101 0.5G - 0.75G
Drug: cefepime 1 g or cefepime 2 g |
Urinary Tract Infections | Allecra | 2017-09-05 | Phase 2 |
| NCT03687255 | COMPLETED | Drug: cefepime/AAI101 combination Drug: Piperacillin/tazobactam |
Urinary Tract Infections | Allecra | 2018-09-24 | Phase 3 |
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