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| Targets |
Bacterial topoisomerase IV (Topo IV) and DNA gyrase (Topo II/DNA gyrase)
Gepotidacin (S enantiomer) targets bacterial DNA gyrase and topoisomerase IV, essential enzymes for bacterial DNA replication and transcription. While its target is similar to that of fluoroquinolone antibacterials, Gepotidacin uses a unique, non-fluoroquinolone binding mechanism. This novel mechanism allows the S-enantiomer to maintain activity against fluoroquinolone-resistant pathogens. The compound has a molecular formula of C₂₄H₂₈N₆O₃ and a molecular weight of 448.52 g/mol. |
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| ln Vitro |
Gepotidacin S enantiomer is a gepotidacin S enantionmer.
In vitro, Gepotidacin (S enantiomer) demonstrates potent antibacterial activity against a range of gram-positive and gram-negative bacteria, including resistant strains such as E. coli and Neisseria gonorrhoeae. It inhibits bacterial DNA gyrase and topoisomerase IV through a unique, non-fluoroquinolone mechanism. The compound exhibits effective antimicrobial activity, making it valuable for research in infectious disease models. Its activity against resistant pathogens makes it a promising candidate for overcoming antibiotic resistance. |
| ln Vivo |
GSK2140944's minimum inhibitory concentrations (MICs) for the six MRSA isolates range from 0.125 to 0.5 mg/L. The range of ELF penetration ratios is 1.1 to 1.4. In neutropenic mice, maximal decreases of 1.1 to 3.1 log10 CFU have been observed. For stasis and 1-log-unit decreases, the mean fAUC/MIC ratios needed are 59.3 ± 34.6 and 148.4 ± 83.3, respectively.
In vivo data for Gepotidacin (S enantiomer) is limited in publicly available sources. Gepotidacin is being developed as an oral and intravenous option for uncomplicated urinary tract infections and sexually transmitted infections, with clinical studies showing promising efficacy and a favorable safety profile. The S enantiomer is expected to maintain the in vivo efficacy of the racemic mixture while potentially offering improved pharmacological properties. However, specific published in vivo studies for the S enantiomer alone are not detailed. |
| Enzyme Assay |
Bacterial Topo IV decatenation assay: Recombinant MRSA or N. gonorrhoeae Topo IV was purified and resuspended in assay buffer containing ATP and kinetoplast DNA (kDNA, substrate for decatenation). Serial concentrations of Gepotidacin (0.01–1 μM) were pre-incubated with the enzyme for 15 minutes at 37°C. The reaction was initiated by adding kDNA, incubated for 30 minutes at 37°C, and terminated by adding SDS-EDTA buffer. DNA products were separated by 1% agarose gel electrophoresis, stained with ethidium bromide, and visualized under UV light. The decatenation activity was quantified by densitometry, and IC50 was calculated as the concentration inhibiting 50% of Topo IV activity [2][4]
The in vitro antibacterial susceptibility assay for Gepotidacin (S enantiomer) is conducted using standard broth microdilution methods according to CLSI guidelines. Bacterial strains including E. coli, N. gonorrhoeae, and other gram-positive and gram-negative organisms are tested. Minimum inhibitory concentrations (MICs) are determined after 16-24 hours of incubation. DNA gyrase and topoisomerase IV inhibition assays use purified enzymes and DNA substrates, with activity measured by monitoring DNA supercoiling or relaxation. |
| Cell Assay |
MIC determination by broth microdilution: Bacterial strains (e.g., MRSA, N. gonorrhoeae, S. pneumoniae) were cultured to mid-logarithmic phase and adjusted to 5×10⁵ CFU/mL in cation-adjusted Mueller-Hinton broth (CAMHB). Gepotidacin was serially diluted (0.008–64 μg/mL) in 96-well plates, and bacterial suspension was added to each well. Plates were incubated at 35°C for 16–20 hours under aerobic conditions (5% CO₂ for fastidious organisms). The MIC was defined as the lowest drug concentration inhibiting visible bacterial growth [1][2][4]
Cellular assays for Gepotidacin (S enantiomer) are conducted in bacterial cell cultures. Bacteria are grown in appropriate media and treated with varying concentrations of the compound. Bacterial growth inhibition is measured by optical density (OD₆₀₀) or colony counting to determine MICs. Time-kill kinetics assays are performed to assess bactericidal activity. Resistance development is evaluated by serial passage in sub-inhibitory concentrations of the compound. |
| Animal Protocol |
Mice: GSK2140944 s.c. in single doses of 6.25, 50, or 200 mg/kg is given to groups of 48 infected mice at 3 h postinoculation (0 h) for neutropenic pharmacokinetic studies. Using a cardiac puncture, blood samples are taken from groups of six mice at five minutes and 0.25, 0.5, 1, 1.5, 2, 3, and 4 hours after the dose for doses of 6.25 or 50 mg/kg, and at five minutes and 0.25, 0.5, 1, 1.5, 2, 4, and 6 hours after the dose for 200 mg/kg[4].
In vivo studies for Gepotidacin (S enantiomer) would typically involve animal models of urinary tract infection or sexually transmitted infection. The compound would be administered orally or intravenously at doses determined by pharmacokinetic studies. Efficacy would be assessed by measuring bacterial clearance from infected tissues and clinical signs of infection. However, specific published in vivo protocols for the S enantiomer are not detailed in the current literature. Gepotidacin has been studied in clinical trials. |
| ADME/Pharmacokinetics |
Pharmacokinetic data for Gepotidacin (S enantiomer) is not extensively reported in publicly available sources. Gepotidacin is being developed as an oral and intravenous option, indicating favorable pharmacokinetic properties. The compound has a molecular weight of 448.52 g/mol. As a small molecule, it is expected to have good oral bioavailability. Detailed PK parameters such as half-life and bioavailability are not available in the current literature for the S enantiomer.
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| Toxicity/Toxicokinetics |
Toxicity data for Gepotidacin (S enantiomer) is derived from the clinical development of Gepotidacin. Clinical studies have shown a favorable safety profile. As with all antibiotics, potential side effects and toxicity would be evaluated in clinical trials. The S enantiomer is expected to have a similar safety profile to the racemic mixture. The compound is intended for research use only and not for therapeutic applications outside of approved clinical use.
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| References |
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| Additional Infomation |
Gepotidacin is a first-in-class triazaacenaphthylene antibacterial targeting bacterial DNA gyrase and topoisomerase IV. Its target is similar to that of fluoroquinolone antibacterials - e.g. [ciprofloxacin] - while being structurally and pharmacologically distinct. By inhibiting two distinct bacterial enzymes, a lower potential for the development of resistance to gepotidacin is expected. In March 2025, gepotidacin was approved by the FDA for the treatment of uncomplicated urinary tract infections in select patients. In December later the same year, the FDA approved another indication for gepotidacin for the treatment of uncomplicated urogenital gonorrhea.
Gepotidacin is a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor. The mechanism of action of gepotidacin is as a Topoisomerase 2 Inhibitor, and Topoisomerase 4 Inhibitor, and P-Glycoprotein Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cholinesterase Inhibitor.
Gepotidacin (S enantiomer) is the S enantiomer of Gepotidacin (GSK2140944), a first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV through a unique, non-fluoroquinolone mechanism. It maintains potent activity against resistant pathogens including E. coli and N. gonorrhoeae. Gepotidacin is being developed as an oral and intravenous option for uncomplicated urinary tract infections and sexually transmitted infections, with clinical studies showing promising efficacy and a favorable safety profile. |
| Molecular Formula |
C24H28N6O3
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|---|---|
| Molecular Weight |
448.517524719238
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| Exact Mass |
448.222
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| Elemental Analysis |
C, 64.27; H, 6.29; N, 18.74; O, 10.70
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| CAS # |
2319789-82-5
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| Related CAS # |
Gepotidacin;1075236-89-3; 2319789-82-5; 1624306-20-2; 1075235-46-9
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| PubChem CID |
100214166
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
0.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
893
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C1C=NC2C=CC(N3C=2N1[C@H](C3)CN1CCC(CC1)NCC1C=C2C(=CN=1)OCCC2)=O
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| InChi Key |
PZFAZQUREQIODZ-IBGZPJMESA-N
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| InChi Code |
InChI=1S/C24H28N6O3/c31-22-4-3-20-24-29(22)15-19(30(24)23(32)13-27-20)14-28-7-5-17(6-8-28)25-11-18-10-16-2-1-9-33-21(16)12-26-18/h3-4,10,12-13,17,19,25H,1-2,5-9,11,14-15H2/t19-/m0/s1
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| Chemical Name |
(3S)-3-[[4-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethylamino)piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione
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| Synonyms |
Gepotidacin S enantiomer; Gepotidacin (S enantiomer); 2319789-82-5; (3S)-3-({4-[({2H,3H,4H-pyrano[2,3-c]pyridin-6-yl}methyl)amino]piperidin-1-yl}methyl)-1,4,7-triazatricyclo[6.3.1.0,4,12]dodeca-6,8(12),9-triene-5,11-dione; (3S)-3-[[4-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethylamino)piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione; ...
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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) |
DMSO : 5 mg/mL (11.15 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (1.11 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 5.0 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: ≥ 0.5 mg/mL (1.11 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 5.0 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: ≥ 0.5 mg/mL (1.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2296 mL | 11.1478 mL | 22.2955 mL | |
| 5 mM | 0.4459 mL | 2.2296 mL | 4.4591 mL | |
| 10 mM | 0.2230 mL | 1.1148 mL | 2.2296 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.
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