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| 25mg |
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Solithromycin (CEM-101; OP1068; CEM101; OP-1068) is a novel and potent ketolide antibiotic with improved antimicrobial effectiveness. It has a broad spectrum of activity against Gram-positive respiratory tract pathogens, including macrolide-resistant strains. Solithromycin is being studied in clinical trials for the treatment of community-acquired pneumonia (CAP) and other infections.
| Targets |
Macrolide
Solithromycin is a novel fluoroketolide antibiotic that binds to the large 50S subunit of the bacterial ribosome. It inhibits protein biosynthesis by interacting with 23S rRNA nucleotides in domains II and V of the 50S ribosomal subunit. Its binding sites are similar to those of telithromycin, but the fluorine at the C-2 position allows for additional ribosomal interactions, enhancing its activity against macrolide-resistant strains [1]. |
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| ln Vitro |
The half-life of solithromycin on the release of TNFα and CXCL8 is 41.6 μM and 78.2 μM, respectively. MMP9 activity is significantly reduced by solithromycin, with an IC50 of 14.9 μM[2].
In monocytic U937 and PBMC cells, levofloxacin (0-333 μM; 72 hours) inhibits the release of TNFα induced by lipopolysaccharide and the activity of matrix metalloproteinase 9 (MMP9) induced by phorbol 12-myristate 13-acetate (PMA). It has no effect on cell viability[2].
Solithromycin was tested against Streptococcus pneumoniae ATCC 49619, Staphylococcus aureus RN1786 (MSSA), Staphylococcus aureus A1024 (MRSA), and Haemophilus influenzae CDC G-79 [1]. The mean 50% inhibitory concentrations (IC50) for inhibition of cell viability, protein synthesis, and growth rate were: - S. pneumoniae: 7.5 ng/mL for all three parameters [1]. - S. aureus (MSSA): 40 ng/mL (protein synthesis), 40 ng/mL (growth rate), 80 ng/mL (CFU) [1]. - S. aureus (MRSA): 48 ng/mL (protein synthesis), 52 ng/mL (growth rate), 85 ng/mL (CFU) [1]. - H. influenzae: 125 ng/mL (mean for all three parameters) [1]. Solithromycin inhibited 50S ribosomal subunit formation in all three organisms. The IC50 for 50S subunit assembly inhibition was 15 ng/mL for S. pneumoniae, 65 ng/mL for MSSA, 93 ng/mL for MRSA, and 230 ng/mL for H. influenzae [1]. Pulse-chase labeling experiments showed that at the IC50 concentration, solithromycin reduced the rate of 50S subunit formation by approximately 50% in S. pneumoniae, >50% in both S. aureus strains, and about 80% in H. influenzae [1]. Agilent Bioanalyzer analysis revealed that solithromycin stimulated turnover and degradation of 23S rRNA in all organisms tested, with the most extensive degradation observed in the MRSA strain. Enhanced degradation of rRNA was also seen in H. influenzae, which naturally contains fragmented 23S rRNA [1]. The compound was a substantially better inhibitor of 50S subunit synthesis in H. influenzae than cethromycin (IC50 1.25 µg/mL) or telithromycin [1]. The IC50 for subunit assembly inhibition was equivalent to the value for protein synthesis inhibition, as previously determined for telithromycin and cethromycin [1]. |
| ln Vivo |
After exposing C57BL/6J mice to cigarette smoke for eight days, oral administration of levofloxacin (100 mg/kg) inhibits the accumulation of inflammatory cells and the production of pro-MMP9[2].
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| Cell Assay |
A 4-fold assay was conducted to examine growth rate, CFU, protein synthesis rates, and ribosomal subunit formation. Cells were grown in appropriate media (TSB for S. aureus; TSB with supplements for H. influenzae and S. pneumoniae) for two doublings in the presence of solithromycin at five different concentrations. Cell growth was monitored using a Klett-Summerson colorimeter. Cell viability was measured by colony counting after serial dilution [1].
For protein synthesis rates, [35S]methionine (1 µCi/mL) was added to cultures before the uridine chase period. Samples were collected at 5-min intervals for 15 min, precipitated with 10% TCA, collected on glass fiber filters, and measured by liquid scintillation counting [1]. For ribosomal subunit formation, RNA was labeled by incubating cells with [3H]uridine (1 µCi/mL, 1 µg/mL) for two doublings. Isotope incorporation was halted by adding uridine (50 µg/mL) followed by a 30-min chase. Cells were lysed (lysozyme freeze-thaw for S. pneumoniae and H. influenzae; lysostaphin for S. aureus) and centrifuged through 5-20% sucrose gradients to separate ribosomal subunits. Fractions were collected and radioactivity measured by liquid scintillation counting [1]. For pulse-chase labeling of subunit synthesis rates, cells were grown with or without solithromycin at the IC50 for each organism. After one doubling, RNA was pulse-labeled with [3H]uridine for 90 s (S. aureus, H. influenzae) or 3 min (S. pneumoniae) and then chased with uridine. Samples were taken at time intervals, and cells were processed for sucrose gradient centrifugation as above [1]. For total RNA analysis, cells were grown with and without solithromycin. Total RNA was isolated (phenol/CHCl3 extraction for S. aureus and S. pneumoniae; Norgen kit for H. influenzae). RNA quality was examined using an Agilent Bioanalyzer 2100 with the RNA 6000 lab chip; 0.5-1 µg of total RNA was loaded per well [1]. |
| Animal Protocol |
Animal Model: C57BL/6J mice (male, 4 weeks)[2]
Dosage: 100 mg/kg Administration: Oral administration; every day; for 8 days Result: prevented the production of pro-MMP9 and neutrophilia brought on by cigarette smoke. |
| References |
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| Additional Infomation |
Solithromycin is an aminoglycoside antibiotic. Solithromycin is a ketolactone antibiotic currently under clinical development for the treatment of community-acquired pneumonia (CAP) and other infections.
Drug Indications It has been studied for the treatment of community-acquired pneumonia (CAP). Treatment of gonococcal infections. Treatment of anthrax, tularemia, and bacterial pneumonia. Solithromycin is a novel fluoroketolide, a semisynthetic derivative of macrolide antibiotics. It lacks the cladinose sugar of macrolides and contains a bridged 11,12-aryl side chain and a fluorine at the C-2 position, which contribute to tighter ribosome binding and improved activity against macrolide-resistant organisms [1]. The compound has been examined for its inhibitory effects on translation in a cell-free system, and a crystal structure revealed its binding interactions with 23S RNA nucleotides in domains II and V in the 50S ribosomal subunit [1]. Like other macrolides and ketolides, solithromycin inhibits 50S ribosomal subunit formation in addition to inhibiting protein synthesis. This dual mechanism of action contributes to its antimicrobial effectiveness [1]. The compound is particularly promising for the treatment of respiratory tract infections due to its potent activity against S. pneumoniae and H. influenzae [1]. Its activity compares favorably with telithromycin and cethromycin and is significantly better than azithromycin and clarithromycin against the organisms tested [1]. |
| Molecular Formula |
C43H65FN6O10
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|---|---|
| Molecular Weight |
845.01
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| Exact Mass |
844.474
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| Elemental Analysis |
C, 61.12; H, 7.75; F, 2.25; N, 9.95; O, 18.93
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| CAS # |
760981-83-7
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| PubChem CID |
25242512
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| Appearance |
Solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
969.2±75.0 °C at 760 mmHg
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| Flash Point |
539.9±37.1 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.591
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| LogP |
3.44
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
60
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| Complexity |
1530
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| Defined Atom Stereocenter Count |
13
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| SMILES |
CC[C@@H]1[C@@]2([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H](C(=O)[C@](C(=O)O1)(C)F)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)N(C(=O)O2)CCCCN4C=C(N=N4)C5=CC(=CC=C5)N)C
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| InChi Key |
IXXFZUPTQVDPPK-QIFQIIIXSA-N
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| InChi Code |
InChI=1S/C43H65FN6O10/c1-12-32-43(8)35(50(40(55)60-43)19-14-13-18-49-23-30(46-47-49)28-16-15-17-29(45)21-28)26(4)33(51)24(2)22-41(6,56-11)37(27(5)36(53)42(7,44)39(54)58-32)59-38-34(52)31(48(9)10)20-25(3)57-38/h15-17,21,23-27,31-32,34-35,37-38,52H,12-14,18-20,22,45H2,1-11H3/t24-,25-,26-,27+,31+,32-,34-,35-,37-,38+,41-,42-,43-/m1/s1
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| Chemical Name |
3aS,4R,7R,9R,10R,11R,13R,15S,15aR)-1-(4-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)butyl)-10-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-7-fluoro-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(7H,9H)-tetraone
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| Synonyms |
CEM 101; OP1068; OP1068; OP 1068; Solithromycin;CEM101; CEM101
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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 : 32~100 mg/mL ( 37.87~118.34 mM )
Ethanol : ~25 mg/mL
H2O : ~1 mg/mL (~1.18 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.96 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 25.0 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: ≥ 2.5 mg/mL (2.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.96 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1834 mL | 5.9171 mL | 11.8342 mL | |
| 5 mM | 0.2367 mL | 1.1834 mL | 2.3668 mL | |
| 10 mM | 0.1183 mL | 0.5917 mL | 1.1834 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 |
| NCT01591447 | COMPLETED | Drug: solithromycin Drug: Solithromycin (CEM-101) |
Uncomplicated Urogenital Gonorrhea | Melinta Therapeutics, Inc. | 2012-05 | Phase 2 |
| NCT02348424 | COMPLETED | Drug: Solithromycin | Gonorrhoea | National Institute of Allergy and Infectious Diseases (NIAID) | 2015-05-05 | Phase 1 |
| NCT02628769 | TERMINATEDWITH RESULTS | Drug: Solithromycin Drug: Placebo |
Pulmonary Disease, Chronic Obstructive | Imperial College London | 2015-07 | Phase 2 |
| NCT02268279 | COMPLETED | Drug: solithromycin | Bacterial Infection | Melinta Therapeutics, Inc. | 2015-01 | Phase 1 |
| NCT02510599 | COMPLETED | Drug: solithromycin | Nonalcoholic Steatohepatitis | Melinta Therapeutics, Inc. | 2015-12 | Phase 2 |
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