| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
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| 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] |
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| ln Vitro |
Enmetazobactam has a MIC50 of 0.125 mg/L and a MIC90 of 64 mg/L, which indicates its strong activity against particular resistance phenotypes. For the majority of strains, cefepime-Enmetazobactam MICs decrease as Enmetazobactam concentrations rise (from 1 to 16 mg/L), indicating that Enmetazobactam's concentration affects the cephalosporin's ability to fight bacteria[1].
- 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 |
Bacterial density reductions of ≥0.5 log10 CFU and ≥1 log10 CFU are observed in neutropenic animals after treatment with cefepime-Enmetazobactam for 12 out of the 20 tested strains. Only four strains exhibit increases in bacterial density, and regardless of the concentration of Enmetazobactam, three of these strains have cefepime-Enmetazobactam MICs of ≥64 mg/L[2].
- 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]
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| 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]
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| Animal Protocol |
Each of the 20 Enterobacteriaceae strains is used to infect three mouse groups. Mice are given humanized cefepime or cefepime-AAI101 treatment regimens two hours after being injected. Subcutaneous injections of 0.2 mL are used to administer each dose. Another set of mice receives normal saline through the same route, at the same volume, and on the same frequency to act as control animals. All animals have their thighs taken 24 hours after treatment starts. All study mice were harvested by first being put to sleep with CO2 exposure and then having their cervical dislocations. Thighs are removed from the sacrifice and homogenized one at a time in regular saline. Using a spiral plater, serial dilutions of thigh homogenates are spread onto Trypticase soy agar containing 5% sheep blood in order to calculate the number of CFU. A third group of three infected but untreated mice is harvested at the start of dosing and used as a 0-hour control, in addition to the previously mentioned treatment and control groups. The measurement of the change in the log10 number of CFU obtained in mice after 24 hours of treatment from the densities observed in the 0-hour control animals determines the efficacy, which is expressed as the change in bacterial density.
- 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 |
Absorption, Distribution and Excretion
The mean (SD) Cmax for cUTI patients with an eGFR greater than or equal to 60 mL/min was 19.8 (6.3) µg/mL. The mean AUC0-last was 75.3 (30.8) μg·h/mL. Approximately 90% of emmetazobacterium is excreted unchanged in the urine. The mean (standard deviation) steady-state volume of distribution (Vss) for cUTI patients with an eGFR ≥ 60 mL/min was 25.26 (9.97) L. The mean (standard deviation) clearance for cUTI patients with an eGFR ≥ 60 mL/min was 7.6 (2.9) L/h. Metabolism/Metabolites Emmetazobacterium is minimally metabolized. Biological half-life In cUTI patients with eGFR ≥ 60 mL/min, the mean (standard deviation) half-life was 2.6 (1.1) hours. - 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, mainly bound to albumin. [2] |
| Toxicity/Toxicokinetics |
Protein Binding
The protein binding rate of emmetazobactam is negligible. - Acute Toxicity: No deaths were observed in mice at doses up to 200 mg/kg. [2] - Subchronic Toxicity: Repeated oral administration (50 mg/kg/day for 28 days) in rats resulted in mild neutrophilia but no significant organ damage. [2] - Clinical Adverse Reactions: In a Phase I clinical trial, emmetazobactam (AAI101) was associated with nausea (12%), headache (8%), and rash (5%). [2] |
| References |
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| Additional Infomation |
Emmetazobacterium is a penicillin sulfone extended-spectrum β-lactamase (ESBL) inhibitor. Because ESBL-producing bacteria can hydrolyze important antibiotics such as penicillins, broad-spectrum cephalosporins, and monocyclic β-lactams, they pose a challenge to the treatment of serious infections. Emmetazobacterium, in combination with cefepime, was first approved by the U.S. Food and Drug Administration (FDA) on February 23, 2024, for the treatment of complicated urinary tract infections (CUTIs). Emmetazobacterium, by inhibiting the breakdown of cefepime by ESBLs, can be used as an alternative therapy to cefepime.
Drug Indications Emmetazobacterium, in combination with cefepime, is indicated for the treatment of complicated urinary tract infections (CUTIs) in adults caused by certain susceptible microorganisms, including pyelonephritis. Mechanism of Action Extended-spectrum β-lactamases (ESBLs) are a class of bacterial serine β-lactamases that hydrolyze third-generation cephalosporins (3GCs), leading to the development of 3GC-resistant bacteria. When used in combination with cefepime, emmetazolamide protects cefepime from degradation by ESBLs and prevents the development of antibiotic resistance. Pharmacodynamics Emmetazolamide is an antibacterial drug effective against most Gram-positive and Gram-negative bacteria. Mechanism of Action: Emmetazolamide (AAI101) covalently binds to serine residues at the active sites of ESBLs and AmpC enzymes, irreversibly inhibiting their activity, thereby preserving the bactericidal activity of cefepime. [1] - Clinical progress: It has entered Phase III clinical trials for the treatment of complicated urinary tract infections (cUTIs) and intra-abdominal infections (IAIs) 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 |
C11H14N4O5S
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|---|---|
| Molecular Weight |
314.317660808563
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| Exact Mass |
314.07
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| Elemental Analysis |
C, 42.03; H, 4.49; N, 17.83; O, 25.45; S, 10.20
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| CAS # |
1001404-83-6
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| Related CAS # |
1379594-98-5 (iodized); 1001404-83-6 (free)
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| PubChem CID |
23653540
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| Appearance |
White to off-white solid powder
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| LogP |
-0.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
21
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| Complexity |
597
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| Defined Atom Stereocenter Count |
3
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| SMILES |
S1([C@@H]2CC(N2[C@@H](C(=O)[O-])[C@]1(C)CN1C=C[N+](C)=N1)=O)(=O)=O
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| InChi Key |
HFZITXBUTWITPT-YWVKMMECSA-N
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| InChi Code |
InChI=1S/C11H14N4O5S/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/t8-,9+,11+/m1/s1
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| Chemical Name |
(2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide
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| Synonyms |
AAI-101, Enmetazobactam;AAI 101; 1001404-83-6; OCID-5090; 80VUN7L00C; AAI101;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 113.3 mg/mL (~360.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+90% (20% SBE-β-CD in Saline): ≥ 2.08 mg/mL (6.62 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1815 mL | 15.9074 mL | 31.8147 mL | |
| 5 mM | 0.6363 mL | 3.1815 mL | 6.3629 mL | |
| 10 mM | 0.3181 mL | 1.5907 mL | 3.1815 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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