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| Targets |
The primary target of DS86760016 is the leucyl‑tRNA synthetase (LeuRS) enzyme, which is essential for protein synthesis in bacteria. By inhibiting LeuRS, DS86760016 blocks the aminoacylation of tRNA‑Leu, thereby interfering with bacterial translation and growth. It shows selectivity for bacterial over mammalian leucyl‑tRNA synthetases.
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| ln Vitro |
At MICs ranging from 0.25 to 2 μg/ml, DS86760016 inhibits a few Gram-negative bacteria. DS86760016 has a minimum inhibitory concentration (MIC) of greater than 32 μg/ml against Gram-positive bacteria. With a MIC90 of 2 μg/ml, DS86760016 is effective against all strains of K. pneumoniae, E. coli, and P. aeruginosa, including susceptible strains[1].
In vitro, DS86760016 inhibits purified LeuRS enzymes from Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii with IC50 values of 0.38, 0.62, and 0.16 microM, respectively. Against whole‑cell MDR bacteria, it exhibits minimum inhibitory concentrations (MICs) of 0.25-2 microg/mL for Gram‑negative strains, while MICs for Gram‑positive bacteria are >32 microg/mL, confirming its Gram‑negative selectivity. |
| ln Vivo |
The drug DS86760016 exhibits considerable spontaneous resistance (FSR) for seven days (7.5-220 mg/kg; sc; q6h)[1]. The intravenous (IV) pharmacokinetic (PK) characteristics of DS86760016 are tested in mouse, rat, monkey, and dog plasma. In mouse, rat, monkey, and dog plasma, DS86760016 exhibits reduced intravenous plasma clearances (CLp) of 11, 29, 5.6, and 4.5 ml/min/kg, respectively. In mice, rats, monkeys, and dogs, the plasma half-lives (t1/2) of DS86760016 are 1.9, 1.5, 8.6, and 8.3 hours, respectively. Due to the reduced plasma clearance, there were higher plasma exposures for DS86760016 in mice, rats, monkeys, and dogs, with dose-normalized areas under the curve after intravenous administration (DNAUCIVs) of 1.5, 0.6, 3.7, and 3.0 μg h kg/ml/mg, respectively[1].
In an immunocompetent female Swiss Webster mouse model of systemic MDR Pseudomonas aeruginosa infection, DS86760016 (7.5-220 mg/kg; s.c.; q6h for 7 days) demonstrated moderate spontaneous resistance frequency. No detailed survival or bacterial burden data have been reported beyond moderate resistance observation. |
| Enzyme Assay |
Purified recombinant LeuRS from E. coli, P. aeruginosa, or A. baumannii is incubated with varying concentrations of DS86760016 (0.001-100 microM) in aminoacylation reaction buffer containing [3H]‑leucine and tRNA‑Leu. Reactions are initiated by addition of ATP, quenched after 10 min, and radiolabeled aminoacyl‑tRNA is captured on filter papers for scintillation counting to determine IC50 values.
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| Cell Assay |
For antibacterial susceptibility testing, overnight cultures of MDR Gram‑negative bacteria are diluted to 5 × 10⁵ CFU/mL in Mueller‑Hinton broth and incubated with DS86760016 (0.125-128 microg/mL) for 18-20 h at 37 degC. MIC is defined as the lowest concentration that completely inhibits visible growth. Parallel cytotoxicity testing on mammalian cell lines (e.g., HEK‑293) can be performed using standard MTT assays.
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| Animal Protocol |
Animal/Disease Models: Immunocompetent female Swiss Webster mice (urinary tract infection, UTI model)[1]
Doses: 7.5, 30, 220 mg/kg Route of Administration: Sc; q6h for 7 days Experimental Results: Bacteria resistant to DS86760016 were detected in a few animals after 1 day of treatment at doses of 7.5 and 30 mg/kg q6h; however, no resistant bacteria were detected at these doses after 7 days of treatment. No resistance was observed in any of the mice treated at a dose of 220 mg/kg q6h. In the mouse systemic infection model, female Swiss Webster mice (n = 10 per group) are infected intraperitoneally with 2 × LD50 of MDR P. aeruginosa. DS86760016 is administered subcutaneously at doses of 7.5, 30, 120, or 220 mg/kg every 6 hours for 7 days. Spontaneous resistance frequency is assessed by plating bacterial cultures recovered from blood and tissues onto drug‑containing agar. |
| ADME/Pharmacokinetics |
DS86760016 exhibits favorable PK with low intravenous plasma clearance (CLp) values of 11, 29, 5.6, and 4.5 mL/min/kg in mouse, rat, monkey, and dog, respectively. Corresponding plasma half‑lives (t½) are 1.9 h (mouse), 1.5 h (rat), 8.6 h (monkey), and 8.3 h (dog). Dose‑normalized area under the curve (DNAUC) values are 1.5, 0.6, 3.7, and 3.0 ug·h·kg/mL/mg in the same species.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for DS86760016 have not been published. Based on its highly selective bacterial LeuRS inhibition and lack of activity against Gram‑positive bacteria, the compound is expected to have a narrow spectrum of action, which may minimize off‑target effects on commensal microbiota. No acute toxicity studies or maximum tolerated dose (MTD) data have been reported.
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| References |
[1]. Purnapatre KP, et al. In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens. Antimicrob Agents Chemother. 2018;62(4):e01987-17. Published 2018 Mar 27.
[2]. Kumar M, et al. DS86760016, a Leucyl-tRNA Synthetase Inhibitor with Activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019;63(4):e02122-18. Published 2019 Mar 27. |
| Additional Infomation |
DS86760016 is a research‑grade antibacterial agent. Its potent activity against MDR Gram‑negative bacteria and favorable cross‑species pharmacokinetic properties make it a promising lead for the development of novel antibiotics targeting leucyl‑tRNA synthetase. As of this writing, it has not entered clinical trials and is not approved for human use. Extensive preclinical efficacy studies in animal models of infection are anticipated.
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| Molecular Formula |
C9H11BCLNO4
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|---|---|
| Molecular Weight |
243.451941728592
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| Exact Mass |
243.046
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| CAS # |
1853176-89-2
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| PubChem CID |
140793266
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
16
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| Complexity |
254
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| Defined Atom Stereocenter Count |
1
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| SMILES |
B1(C2=C(C=CC3=C2OCO3)[C@H](O1)CN)O.Cl
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| InChi Key |
FYHCZFHPLJMBAX-OGFXRTJISA-N
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| InChi Code |
InChI=1S/C9H10BNO4.ClH/c11-3-7-5-1-2-6-9(14-4-13-6)8(5)10(12)15-7;/h1-2,7,12H,3-4,11H2;1H/t7-;/m1./s1
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| Chemical Name |
[(3S)-1-hydroxy-3H-[1,3]dioxolo[4,5-g][2,1]benzoxaborol-3-yl]methanamine;hydrochloride
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 4.1076 mL | 20.5381 mL | 41.0762 mL | |
| 5 mM | 0.8215 mL | 4.1076 mL | 8.2152 mL | |
| 10 mM | 0.4108 mL | 2.0538 mL | 4.1076 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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