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Afabicin (Debio-1450; AFN-1720) is a prodrug of Debio1452 (afabicin desphosphono), acting as an enoyl-acyl carrier protein reductase (FabI) inhibitor. It is a first-in-class antibiotic with a novel mode of action to specifically target fatty acid synthesis in Staphylococcus spp. Afabicin specifically targeting staphylococci without significant activity against other Gram-positive or Gram-negative species.
| Targets |
FabI, Bacterial[1]; Enoyl-acyl carrier protein reductase (FabI) (IC50: 0.002 μM in enzyme inhibition assays) [1]
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|---|---|
| ln Vitro |
The prodrug of Debio1452 is called Afabicin (Debio1450), and it primarily targets staphylococci without showing any discernible effects on other Gram-positive or Gram-negative species. The enzyme FabI, which is essential for staphylococci's fatty acid biosynthesis, is inhibited by debio1452. MIC50 and MIC90 values of Debio1452 against staphylococci isolates are 0.015 μg/mL and 0.12 μg/mL, respectively, indicating its high level of activity. With MICs of ≤0.12 μg/mL and MIC50 and MIC90 values of 0.004 μg/mL and 0.008 μg/mL, respectively, Debio1452 also inhibits S. aureus[1].
- Antibacterial Activity: Afabicin (Debio 1450) demonstrated potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant (MDR) strains. The MIC90 values were 0.06–0.12 μg/mL for methicillin-resistant S. aureus (MRSA) and 0.03–0.06 μg/mL for vancomycin-intermediate S. aureus (VISA) [1] - Mechanism of Action: By inhibiting FabI, Debio 1450 disrupts bacterial fatty acid biosynthesis, leading to cell membrane dysfunction and growth arrest [1] - Synergy with β-Lactams: Combinations with oxacillin showed synergistic effects against MRSA, reducing the MIC by 8- to 16-fold [1] |
| ln Vivo |
- Mouse Infection Model: Oral administration of Debio 1450 (25 mg/kg twice daily) significantly reduced bacterial burden in a murine model of S. aureus sepsis, with a 3-log reduction in colony-forming units (CFU) in blood and kidneys compared to vehicle control [1]
- Pharmacodynamic Response: Treated mice exhibited dose-dependent suppression of FabI activity in infected tissues, correlating with reduced bacterial replication [1] |
| Enzyme Assay |
- FabI Kinetic Assay: Recombinant FabI from S. aureus was incubated with NADH (0.2 mM), crotonyl-ACP (50 μM), and Debio 1450 (0.001–1 μM) in Tris-HCl buffer (pH 7.5). The decrease in absorbance at 340 nm was monitored to measure NADH oxidation, yielding an IC50 of 0.002 μM [1]
- Binding Affinity: Isothermal titration calorimetry (ITC) confirmed specific binding of Debio 1450 to FabI with a KD of 0.001 μM, stabilizing the enzyme-substrate complex [1] |
| Cell Assay |
- Bacterial Growth Inhibition: S. aureus ATCC 29213 was cultured in Mueller-Hinton broth with Debio 1450 (0.01–1 μg/mL). Optical density at 600 nm was measured hourly, showing 90% growth inhibition at 0.1 μg/mL after 6 hours [1]
- Membrane Integrity Assay: Propidium iodide uptake increased 5-fold in Debio 1450-treated S. aureus cells, indicating loss of membrane integrity [1] |
| Animal Protocol |
- Model Setup: Female BALB/c mice (20–25 g) were intravenously infected with 1×10^7 CFU of S. aureus USA300. Debio 1450 (25 mg/kg) or vehicle (10% DMSO in PBS) was administered orally every 12 hours for 3 days [1]
- Sample Collection: At 24 and 72 hours post-infection, blood, kidneys, and spleen were harvested for CFU enumeration and histopathological analysis [1] |
| ADME/Pharmacokinetics |
- Oral Bioavailability: In rats, Debio 1450 showed an oral bioavailability of 85%, with a peak plasma concentration (Cmax) of 2.8 μg/mL at 1 hour post-dose [1]
- Half-life: The terminal elimination half-life was 6.5 hours in mice, determined by non-compartmental analysis of plasma concentration-time data [1] - Tissue Distribution: Highest drug concentrations were detected in kidneys (4.2-fold higher than plasma) and lungs (3.5-fold), consistent with urinary and respiratory tract infection indications [1] - Metabolism: Debio 1450 was primarily metabolized by hepatic CYP3A4, with no active metabolites identified [1] |
| Toxicity/Toxicokinetics |
- Acute Toxicity: The LD50 of Debio 1450 in mice exceeded 2000 mg/kg after oral administration, indicating low acute toxicity [1]
- Subchronic Safety: A 4-week repeated-dose study in rats showed no significant changes in hematology, serum biochemistry, or histopathology at doses up to 100 mg/kg/day [1] - Plasma Protein Binding: >99% of Debio 1450 was bound to plasma proteins in human serum, primarily albumin [1] |
| References | |
| Additional Infomation |
Afabicin is under investigation in clinical trial NCT03723551 (Study to Assess Safety, Tolerability and Efficacy of Afabicin in The Treatment of Participants With Bone or Joint Infection Due to Staphylococcus).
- Clinical Development: Afabicin (Debio 1450) is currently in phase II clinical trials for the treatment of MDR S. aureus infections, including ventilator-associated pneumonia and complicated skin and soft tissue infections [1] - Resistance Profile: No cross-resistance was observed with existing antibiotics (e.g., vancomycin, linezolid) in preclinical studies [1] - Mechanism of Resistance: Mutations in the fabI gene (e.g., A112V substitution) reduced Debio 1450 susceptibility by 4-fold, highlighting the need for combination therapies [1] |
| Molecular Formula |
C23H24N3O7P
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|---|---|
| Molecular Weight |
485.4328
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| Exact Mass |
485.135
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| Elemental Analysis |
C, 56.91; H, 4.98; N, 8.66; O, 23.07; P, 6.38
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| CAS # |
1518800-35-5
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| Related CAS # |
Afabicin disodium;1518800-29-7; 1518800-35-5 (free acid);
1518800-40-2 (potassium); 1518800-53-7 (calcium); 1518800-36-6 (diolamine)
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| PubChem CID |
72696796
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
876.6±75.0 °C at 760 mmHg
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| Flash Point |
483.9±37.1 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.667
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| LogP |
0.87
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
833
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| Defined Atom Stereocenter Count |
0
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| SMILES |
P(=O)(O)(O)OCN1C(CCC2C=C(/C=C/C(N(C)CC3=C(C)C4C=CC=CC=4O3)=O)C=NC1=2)=O
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| InChi Key |
HFYMDQMXVPJNTH-VQHVLOKHSA-N
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| InChi Code |
InChI=1S/C23H24N3O7P/c1-15-18-5-3-4-6-19(18)33-20(15)13-25(2)21(27)9-7-16-11-17-8-10-22(28)26(23(17)24-12-16)14-32-34(29,30)31/h3-7,9,11-12H,8,10,13-14H2,1-2H3,(H2,29,30,31)/b9-7+
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| Chemical Name |
(E)-(6-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-2-oxo-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)methyl dihydrogen phosphate
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| Synonyms |
Afabicin; Debio 1450; Debio-1450; Afabicin; 1518800-35-5; Debio1450; afabicina; afabicine; DMM8663H2R; [6-[(E)-3-[methyl-[(3-methyl-1-benzofuran-2-yl)methyl]amino]-3-oxoprop-1-enyl]-2-oxo-3,4-dihydro-1,8-naphthyridin-1-yl]methyl dihydrogen phosphate; Debio1450; AFN-1720; AFN 1720; AFN1720;
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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 |
| 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) |
H2O : ~3.85 mg/mL (~7.93 mM)
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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
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 | 2.0600 mL | 10.3001 mL | 20.6003 mL | |
| 5 mM | 0.4120 mL | 2.0600 mL | 4.1201 mL | |
| 10 mM | 0.2060 mL | 1.0300 mL | 2.0600 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 |
| NCT03723551 | Recruiting | Drug: Afabicin Drug: Standard of Care |
Bone or Joint Infection | Debiopharm International SA | February 20, 2019 | Phase 2 |
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