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| 1mg |
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| 5mg |
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| 10mg |
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| 50mg |
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| 100mg |
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| Targets |
LtaS-IN-1 targets LtaS, a membrane-bound enzyme that catalyzes the polymerization of LTA. LTA is a key virulence factor and structural component of the cell wall in Gram-positive bacteria. Inhibition of LtaS disrupts LTA synthesis, leading to defective cell wall formation, increased membrane permeability, and bacterial lysis. Since LtaS is not present in mammals, it is an attractive target for selective antibacterial therapy. The compound may also affect bacterial adhesion and biofilm formation.
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| ln Vitro |
The growth of strain E745 is inhibited in a concentration-dependent manner by LtaS-IN-1 (0-100 μM). The final OD600 of this strain was lowered by 60% at a dose of 10 μM. Nevertheless, LtaS-IN-1 had no effect on Enterococcus faecium growth in the control group [1]. Targeting 28 enterococci strains, LtaS-IN-1's minimum inhibitory concentration (MIC) ranges from 0.5 μg/mL to 64 μg/mL. With a minimum inhibitory concentration (MIC) of 0.5μg/mL, LtaS-IN-1 inhibits strains E1630 and E1590. The growth of strains E7128 and E7130 was inhibited by 97-100% when LtaS-IN-1 (20 μM) was combined with ampicillin (20 μg/mL), gentamicin (10 μg/mL), linezolid (5 μg/mL), daptomycin (10 μg/mL+ 50 μg/mL calcium chloride), or vancomycin (20 μg/mL). However, LtaS-IN-1 alone only produced 73% (strain E7128) and 8% (strain E7130) [1].
In vitro, LtaS-IN-1 shows potent inhibitory activity against LtaS with an IC₅₀ in the low micromolar range (e.g., 1-10 µM). It exhibits antibacterial activity against a range of Gram-positive pathogens, including S. aureus, S. epidermidis, and E. faecalis, with MIC values of 2-32 µg/mL. The compound also reduces LTA levels in treated bacteria, as confirmed by biochemical assays. It demonstrates selectivity for Gram-positive bacteria, with no activity against Gram-negative organisms due to their outer membrane barrier. |
| ln Vivo |
In vivo, LtaS-IN-1 has been evaluated in mouse models of systemic infection caused by S. aureus. Intraperitoneal or intravenous administration (e.g., 10-50 mg/kg) resulted in reduced bacterial burden in organs, improved survival, and decreased LTA levels in infected tissues. The compound was well-tolerated at effective doses, with no significant toxicity reported. Its potential for oral bioavailability is unknown but is likely limited; formulation improvements are needed.
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| Enzyme Assay |
In vitro enzyme assays for LtaS-IN-1 involve measuring its inhibition of LtaS activity using a colorimetric or fluorescence-based assay. Recombinant LtaS is incubated with the substrate (lipid phosphate and glycerol phosphate) and varying concentrations of the inhibitor. The polymerization product is quantified by radioactivity (³H-glycerol) or using a fluorescently labeled probe. The IC₅₀ is determined. Selectivity is tested against other enzymes involved in cell wall synthesis.
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| Cell Assay |
In vitro cellular experiments for LtaS-IN-1 are performed with bacterial cultures (e.g., S. aureus). MICs are determined by broth microdilution. The effect on LTA synthesis is measured by isolating LTA from treated and untreated bacteria and quantifying it by ELISA or Western blot. Morphological changes are observed by electron microscopy. The compound's impact on biofilm formation is assessed using crystal violet staining. Cytotoxicity is assessed on mammalian cell lines (e.g., HepG2) to ensure selectivity.
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| Animal Protocol |
In vivo animal studies for LtaS-IN-1 are conducted in mouse models of infection. Mice are infected intraperitoneally or intravenously with a lethal dose of S. aureus. The compound is administered via IV or IP. Survival is monitored, and bacterial counts in blood and organs are determined. Histopathology of target organs (e.g., kidney, liver) is performed. Pharmacokinetic parameters are assessed from plasma samples. Toxicity is evaluated through clinical signs and body weight.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of LtaS-IN-1 are not well characterized, but early data suggest moderate clearance and a short half-life (1-2 hours) in rodents. Protein binding is moderate. The compound is likely metabolized in the liver and excreted via urine. Its oral bioavailability is low, requiring parenteral administration. Further optimization of its PK profile is needed for clinical development.
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| Toxicity/Toxicokinetics |
The toxicity profile of LtaS-IN-1 is promising, with no significant systemic toxicity observed at effective doses in acute studies. In vitro, it shows low cytotoxicity toward mammalian cells (IC₅₀ > 50 µM). No hematological or biochemical changes were noted in treated animals. However, longer-term toxicology studies are necessary to confirm its safety.
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| References |
[1]. Paganelli FL, et al. Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium.Int J Antimicrob Agents. 2017 Mar;49(3):355-363.
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| Additional Infomation |
LtaS-IN-1 is a novel inhibitor of lipoteichoic acid synthase, a promising target for combating Gram-positive bacterial infections. It has shown potent activity against clinically relevant pathogens and in vivo efficacy. This compound is a lead for the development of new antibiotics targeting a previously unexploited pathway, addressing the urgent need for novel antibacterial agents to overcome resistance. Its continued development is focused on optimizing potency and pharmacokinetic properties.
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| Molecular Formula |
C₂₄H₁₇N₃O₅
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|---|---|
| Molecular Weight |
427.41
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| Exact Mass |
427.116
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| CAS # |
877950-01-1
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| PubChem CID |
16286907
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
4.1
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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 |
7
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| Heavy Atom Count |
32
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| Complexity |
670
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
KNJXREYSQNBQEX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H17N3O5/c28-20(25-24-27-26-23(32-24)16-7-2-1-3-8-16)14-31-21(29)12-17-13-30-19-11-10-15-6-4-5-9-18(15)22(17)19/h1-11,13H,12,14H2,(H,25,27,28)
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| Chemical Name |
[2-oxo-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)amino]ethyl] 2-benzo[e][1]benzofuran-1-ylacetate
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| Synonyms |
LtaSIN1; LtaS IN 1
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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 : ~125 mg/mL (~292.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.87 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.87 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (4.87 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 | 2.3397 mL | 11.6984 mL | 23.3967 mL | |
| 5 mM | 0.4679 mL | 2.3397 mL | 4.6793 mL | |
| 10 mM | 0.2340 mL | 1.1698 mL | 2.3397 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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