ChemicalBook CAS DataBase List 103060-53-3

103060-53-3

Name	Daptomycin
CAS	103060-53-3
EINECS(EC#)	600-389-2
Molecular Formula	C72H101N17O26
MDL Number	MFCD28968054
Molecular Weight	1620.68
MOL File	103060-53-3.mol

Chemical Properties

Melting point	202-204?C
Boiling point	2078.2±65.0 °C(Predicted)
density	1.45±0.1 g/cm3(Predicted)
Fp	87℃
storage temp.	Store at -20°C
solubility	methanol: soluble5mg/mL
form	powder
pka	4.00±0.10(Predicted)
color	colorless to faint yellow
biological source	Streptomyces roseosporus
λmax	260nm(EtOH)(lit.)
Merck	14,2823
Sequence	Dec-Trp-{d-Asn}-Asp-Thr-Gly-{Orn}-Asp-{d-Ala}-Asp-Gly-{d-Ser(Me)}-Glu-{Kynurenine} (Lactone: Thr4-Kynurenine13)
Stability:	Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
InChIKey	DOAKLVKFURWEDJ-RWDRXURGSA-N

Safety Data

Symbol(GHS)	GHS07
Signal word	Warning
Hazard statements	H315-H319-H335
Precautionary statements	P280-P302+P352-P362+P364
WGK Germany	3
RTECS	HB5626000
HS Code	29419090
Storage Class	11 - Combustible Solids
Toxicity	LD50 i.v. in mice: 600 mg/kg (Debono) less more

Hazard Information

Chemical Properties

Off-White to Light Yellow Solid

Definition

ChEBI: A polypeptide comprising N-decanoyltryptophan, asparagine, aspartic acid, threonine, glycine, ornithine, aspartic acid, D-alanine, aspartic acid, glycine, D-serine, threo-3-methylglutamic ac d and 3-anthraniloylalanine (also known as kynurinine) coupled in sequence and lactonised by condensation of the carboxylic acid group of the 3-anthraniloylalanine with the alcohol group of the threonine residue.

Description

Daptomycin is the first entry of a new class of cyclic lipopeptide antibiotics that disrupts multiple aspects of bacterial membrane function including disruption of membrane potential and amino acid transport, inhibition of lipoteichoic acid synthesis and inhibition of peptidoglycan synthesis. It is indicated for the treatment of complicated skin and skinstructure infections (cSSSI) caused by a range of Gram-positive bacteria. This is distinct from previous classes of antibiotics that inhibit bacterial cell wall biosynthesis, bacterial DNA replication, and folate coenzyme biosynthesis. Due to this unique mechanism, cross-resistance has not been noted with any other class of antibiotics. It is produced by the fermentation of Streptomyces roseporus. The fatty acid side chain is a key determinant of acute toxicity, with the ten-carbon chain least acutely toxic to mice. Daptomycin has shown efficacy in a variety of animal models versus several Grampositive infectious agents including methicillin-susceptible S aureus, vancomycinresistant E faecalis, spyogenes and S pneumoniae. It retains in vitro activity against methicillin, vancomycin and linezolid-resistant strains including Staphylococcus aureus (MRSA and VRSA), which is the leading cause of hospital-acquired infections (nosocomial infections (Nis)). The MIC values against Gram-positive pathogens are relatively low, ranging from 0.06 to 2.0 mg/mL. In two clinical studies treating patients (ca. 1090 for both arms of both studies) with complicated skin and soft tissue infections (cSSTIs) in which gram-positive pathogens were suspected and parenteral antibiotics were required, daptomycin provided similar clinical success rates as compared to standard therapy with vancomycin or semisynthetic penicillins such as cloxacillin, oxacillin, or flucloxacillin. The daptomycin treated group showed more rapid improvement as noted by scoring on day three or four and also had a shorter duration of treatment versus the standard therapy group (7 vs 8 days). It is dosed once daily (4 mg/kg/day) by intravenous infusion and has a half-life of 8.1 h. It is primarily cleared renally and thus requires dosing adjustments for those with severe renal insufficiency (CLCR ,30 mL/min). Clinical safety of daptomycin is similar to other antibiotics.

Originator

Lilly (US)

Brand name

Cubicin (Cubist).

Synthesis Reference(s)

[1]Grünewald, J., Sieber, S. A., Mahlert, C., Linne, U., & Marahiel, M. A. (2004). Synthesis and Derivatization of Daptomycin: A Chemoenzymatic Route to Acidic Lipopeptide Antibiotics. Journal of the American Chemical Society, 126(51), 17025–17031. https://doi.org/10.1021/ja045455t
[2]Lam, H. Y., Zhang, Y., Liu, H., Xu, J., Wong, C. T. T., Xu, C., & Li, X. (2013). Total Synthesis of Daptomycin by Cyclization via a Chemoselective Serine Ligation. Journal of the American Chemical Society, 135(16), 6272–6279. https://doi.org/10.1021/ja4012468
[3]Miao, V., Coëffet-LeGal, M.-F., Brian, P., Brost, R., Penn, J., Whiting, A., Martin, S., Ford, R., Parr, I., Bouchard, M., Silva, C. J., Wrigley, S. K., & Baltz, R. H. (2005). Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology, 151(5), 1507–1523. https://doi.org/10.1099/mic.0.27757-0

Pharmaceutical Applications

A semisynthetic lipopeptide derived from a fermentation product of Streptomyces roseosporus.
Daptomycin is a cyclic peptide with a lipophilic tail and thus resembles the polymyxins structurally. Its useful activity is restricted to Gram-positive cocci, notably Staph. aureus and its chief attraction is that it retains activity against multiresistant strains. Its activity in vitro is greatly potentiated by the presence of calcium (but not magnesium) ions and in these conditions it is more potently bactericidal than the glycopeptides.

Clinical Use

Daptomycin is a fermentation product having a cyclic lipopeptide structure. It is primarily active against Gram-positive infections, especially those involved in skin/skin structure infections. It is given IV but must be administered over a period of 30 minutes or more. It binds to cell membranes and causes depolarization, which interrupts protein, DNA, and RNA synthesis. Daptomycin is bactericidal. Although resistance can be achieved in vitro, resistance has been slow to emerge in the clinic. Patients should be monitored for muscle pain or weakness, because some incidence of elevated serum creatinine phosphokinase is associated with its use. A small number of clinical trial patients also developed conditions related to decreases in nerve conduction (e.g., paresthesias and Bell's palsy). Daptomycin is eliminated primarily by the kidney, so dose adjustment may be necessary in cases of renal insufficiency.

Side effects

It is generally well-tolerated, but gastrointestinal side effects, headache and various other adverse reactions occur with varying frequency. Less commonly, but more seriously, myalgia, muscle weakness and myositis may occur requiring regular monitoring of creatine kinase during treatment. Rhabdomyolysis has been reported, but is very rare.

Synthesis

Daptomycin derivatives are generated chemoenzymatically using the recombinant cyclization domain of the Streptomyces coelicolor calcium-dependent antibiotic nonribosomal peptide synthetase as a catalyst, and protected daptomycin is prepared by coupling the undecapeptide core with activated dipeptide esters followed by deprotection and purification[1][3]. Total synthesis of daptomycin is achieved via an efficient macrocyclization through a chemoselective serine ligation, and the product is also produced by heterologous expression of the dpt gene cluster in Streptomyces lividans TK64 followed by isolation from fermentation broth[2][3].

Metabolism

In-vitro studies indicate that daptomycin is not metabolised by, and does not affect, the cytochrome P450 isoenzyme system. Little or no metabolism is thought to take place although 4 minor metabolites have been detected in the urine
Daptomycin is excreted mainly via renal filtration with about 78% and 6% of a dose recovered in the urine and faeces, respectively

storage

-20°C

References

1) Jung?et al. (2004),?Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin; Chem. Biol.,?11?949 2) Steenbergen?et al. (2005),?Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections; J. Antimicrob. Chemother.,?55?283

Questions And Answer

Antibiotic
Daptomycin is a kind of cyclic lipopeptide antibiotics with novel structure. It is extracted from the Streptomyces fermentation broth. It was discovered by Eli Lilly Company in the 1980s, and successfully developed in 1997 by Cubist Pharmaceuticals. It not only having a novel chemical structure but also has mode of action which is different from any antibiotic approved before: it inhibits cell by disrupting the transport of amino acids through cell membrane, thereby blocking the cell wall peptidoglycan biosynthesis and changing the nature of the cell membrane. It can destroy the bacterial cell membrane function in many aspects, and quickly kill gram-positive bacteria. In addition to the role of taking effect on most clinically relevant gram-positive bacteria, more importantly, Daptomycin has a potent efficacy in treating isolated strains which have shown signs of resistance to methicillin, vancomycin and linezolid. This property is of great clinical significance to patients suffering from severe infection.
In September 2003, the US Food and Drug Administration had approved for the first time that daptomycin could be applied for the treatment of severe skin infections. In March 2006, it was approved for treating infectious diseases.
In January 2006, it is approved by European Commission for the treatment of certain complicated skin and soft tissue infections caused by gram-positive bacteria.
On September 6, 2007, Cubist Pharmaceuticals announced that the European Union has approved its antibacterial drug, Cubicin for the treatment of right heart endocarditis caused by Staphylococcus aureus infections and complicated skin and soft tissue infection related diseases caused by Staphylococcus aureus.
On July 29, 2010, the US Food and Drug Administration (FDA) released information on the issue that intravenous injection of daptomycin (daptomycin, produced by Cubist Pharmaceuticals, with brand name “Cubicin”) may cause eosinophilic pneumonia in order to remind the patients and medical professionals. Eosinophilic pneumonia is a rare and very severe disease whose symptoms include fever, cough, shortness of breath and difficulty in breathing. ;
Antibacterial effect
Studies have shown that daptomycin has a similar antibacterial spectrum antibacterial with vancomycin which mainly has a strong inhibitory effect against Gram-positive bacteria, MIC of Staphylococcus spp: 0.125~0.5 μg/ml; MIC for gram bacterial spp: 0.06~0.5μg/ml; MIC for enterococci: 0.25~2.0 μg/ml. Daptomycin also has a broad antibacterial spectrum against Gram-positive anaerobic bacteria: MIC for Peptostreptococcus spp: 0.12μg/ml; MIC for Clostridium spp.: 0.5 μg/ml; MIC for Lactobacillus spp.: 1 μg/ml.
Daptomycin has a good antibacterial activity on a variety of antibiotic-resistant bacteria, for example, the MIC for methicillin-resistant carbamoyl Staphylococcus (MRSA) is 0.06~0.5 μg /mL; MIC for methicillin-resistant Staphylococcus is 0.0625~1 μg/ml; MIC for oxacillin resistant strains of Staphylococcus is 0.12~0.5 μg/ml; MIC for highly aminoglycosides-resistant enterococci is 2.5μg/mL, MIC for GmrBIa-enterococci is 0.5~1 μg/mL; MIC for glycopeptide antibiotic-resistant enterococci is 1~2 μg /mL. ;
Toxicology
According to the information of Eli Lilly pharmaceutical laboratories, daptomycin is a relatively safe, low toxic antibiotic. LD 50 of Mouse is 142~159 mg/kg (Dog 200 mg/kg). It is non-lethal but can cause weight loss and loss of appetite; LD 50 of Monkey is 25~200 mg/kg. The main symptoms are lethargy, muscle weakness, ataxia, increase in creatinine phosphokinas, and slight irritation after skin and eye contact. With different dosage (25~125 mg/kg) of drugs being administrated (intravenously) to mice for a month, each dose group all exhibited the degeneration of both renal cortical tubular epidermis and skeletal muscle. It was also observed that sciatic nerve degeneration occurred at the dose group of 150 mg/kg dos. But It has no effect on fertility and also has no teratogenic effects. During six months of chronic toxicity test, the dog was intravenously injected with daptomycin at doses of 2, 10, 40 mg/(kg·d), respectively. Only the dogs at 40 mg /(kg·d) dose group exhibited a loss of knee jerk reaction and moderate degeneration of axonal and mild declining nerve transmission rate. But these functions can be recovered after the withdrawal for two weeks. A single around of dose at 2.0mg/kg has no effect on human muscles and nervous system. ;
Pharmacokinetics
Healthy volunteers were administrated (intravenous injection) of six different doses in the range of 0.5~6.0 mg/kg and 1.0 mg/kg 14C marked daptomycin, the results showed that daptomycin has a relatively long T1/2 in vivo (T1/2 = 6~8 h), a relatively small volume of distribution (V = 0.1~0.2 L/kg), and a renal clearance CLr of 0.17~0.2 ml/(min?kg). Daptomycin is mainly presented in the blood in the form of non-metabolized original drug with kidney as the major metabolic organ. About 78% of daptomycin is excreted in the urine. There are metabolites of daptomycin presented in the urine. The distribution pattern of daptomycin in the body is not fully understood. Patients of septicemia and endocarditis needs to subject to intravenous administration of daptomycin at a dose of 3mg/kg in every 12 h. Compared with healthy volunteers, people in daptomycin group had a average peak blood concentration (cmax): 35.45, which is lower than in healthy people. They also had an increased steady-state volume of distribution (Vss = 0.21) and a 22% increased clearance rate (CL). ;
In vivo activity and clinical application
This product is mainly used in the treatment of endocarditis, sepsis, peritonitis and urinary tract infections caused by Staphylococcus, Streptococcus, and Enterococcus. It is of particular importance in the treatment of endocarditis caused by various drug-resistant strains. Animal experiments showed that the application of daptomycin in treatment of endocarditis, peritonitis, pneumonia, and osteomyelitis caused by MRSA or other resistant strains caused by, yields a equivalent or even better effect than vancomycin. Moreover, daptomycin has a longer in vivo t1/2 long and has a smaller side effect and therefore it has considerable clinical value. In October 1990, it was reported about the first case of the failure of daptomycin in treatment of S. aureus-caused endocarditis which is likely due to the high affinity of daptomycin to the proteins (90%), the low dose of applied drug and different pharmacokinetic parameters of patients with healthy people. Deepened study of the pharmacology and clinical application of daptomycin is still ongoing. ;
Resistance
The incidence of the occurrence of daptomycin-resistant strains is low with only a mild resistance. In the in vitro selection of daptomycin-resistant strains from Streptococcus pneumoniae, Enterococcus, Staphylococcus, the incidence of drug-resistant strains of Streptococcus pneumoniae was the highest with 1.2 × 10-6 (16MIC) while Staphylococcus has the lowest incidence of drug-resistant strains which was only 7.0 × 10-9 (8MIC). General the MIC is only increased by 8 to 32 times. Using medium supplied no antibiotics for continuous passage of three generations can reduce the resistance ability to 1/2 to 1/4. In a rabbit model of endocarditis, after treatment of daptomycin, 13% of the rabbit produces daptomycin-resistance of Staphylococcus but with weakened resistance, indicating the stability of daptomycin resistance may involve multiple point mutations.
The above information is edited by the Chemicalbook of Dai Xiongfeng. ;
Drug Interactions
Daptomycin has synergistic effect when used in combination with netilmicin, amikacin, imipenem, and fosfomycin. This can improve the antibacterial activity. Combination with teicoplanin, vancomycin has a good antibacterial activity against Sma GmrBla-enterococci. Combination of daptomycin with gentamicin also has synergistic effects on resistant glycopeptide antibiotics-resistant Streptococcus faecalis. This has been demonstrated in animal models. Combination of daptomycin and tobramycin for therapy can reduce the nephrotoxicity of the latter drug, which is just opposite with vancomycin. ;
Uses
Pharmaceutical intermediates, used in the treatment of concurrent skin and skin structure infections caused by a number of Gram-positive caused by susceptible strains. ;

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103060-53-3

Chemical Properties

Safety Data

Hazard Information

Chemical Properties

Definition

Description

Originator

Brand name

Synthesis Reference(s)

Pharmaceutical Applications

Clinical Use

Side effects

Synthesis

Metabolism

storage

References

Questions And Answer

Antibiotic

Antibacterial effect

Toxicology

Pharmacokinetics

In vivo activity and clinical application

Resistance

Drug Interactions

Uses

Spectrum Detail

Supplier

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