Arbekacin

Description

Arbekacin is a semi-synthetic derivative of dibekacin useful in the treatment of bacterial infections. This aminoglycoside is active against a broad spectrum of bacteria, including some of the gentamycin-, kanamycin-, and tobramycin-resistant pathogens. Compared to amikacin and dibekacin, ototoxicity is reportedly milder.

Originator

Inst. Microbial Chemistry (Japan)

Definition

ChEBI: A kanamycin that is kanamycin B bearing an N-(2S)-4-amino-2-hydroxybutyryl group on the aminocyclitol ring.

Manufacturing Process

13.53 g (30 mmole) of 3',4'-dideoxykanamycin (abbreviated as DKB) in the form of the free base was dissolved in 135 ml of water, and to this solution was added dropwise 5.61 g (33 mmole) of benzyloxycarbonyl chloride over 1 h under stirring and under ice-cooling (0°-5°C). After the addition, the mixture was further stirred for 1 h at room temperature and filtered to remove the precipitate.
The filtrate was washed with 135 ml of ethyl ether. The aqueous phase was neutralized by addition of aqueous ammonia and then concentrated under reduced pressure. The concentrated solution was passed through a column of 480 ml of a cation-exchange resin essentially consisting of a copolymer of methacrylic acid and divinylbenzene (available under a trade name "Amberlite CG 50", a product of Rohm and Haas Co., U.S.A. the ammonium form) to effect the adsorption of the benzyloxycarbonylated DKB by the resin. The resin column was washed with water (1920 ml) and then eluted with 0.1 N aqueous ammonia. 960 ml of the first running of the eluate was discarded, and the subsequently running fraction of the eluate amounting to 780 ml was collected, concentrated and freeze-dried to give 5.43 g (yield 31%) of 6'-Nbenzyloxycarbonyl DKB as a colorless powder, melting point 113°-115°C (dec.).
4.04 g (6.9 mmole) of the 6'-N-benzyloxycarbonyl DKB was dissolved in 26 ml of water, and to this solution was added a solution of 2.94 g (8 mmole) of Nhydroxysuccinimide ester of (S)-4-benzyloxycarbonylamino-2-hydroxybutyric acid in 45 ml of dimethoxyethane. The admixture was stirred at room temperature for 90 min and then the reaction mixture was concentrated to dryness. The residue was taken up in a volume of water and the aqueous solution was poured into a column of 560.0 g of silica gel. The elution was conducted using methanol-chloroform-17% aqueous ammonia (4:2:1), and such eluate fractions containing the unreacted materials were discarded. The fractions containing the mixed acylated products were collected and concentrated to give 5.63 g of the mixed acylated products. The mixed acylated products were dissolved in a mixture of 67 ml of glacial acetic acid, 63 ml of methanol and 17 ml of water, and the solution so obtained was admixed with 1.6 g of 5% palladium-carbon and hydrogenated with hydrogen at atmospheric pressure for 4 h to remove the benzyloxycarbonyl groups of the acylated products. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to under reduced pressure to give 5.20 g of a powder of the acetate of the acylated products comprising 1-N- [(S)-4-amino-2-hydroxybutyryl] DKB acetate.
The aqueous solution of 1-N-[(S)-4-amino-2-hydroxybutyryl] DKB acetate was poured into a column of 250 ml of a cation-exchange resin made of a copolymer of methacrylic acid and divinylbenzene (commerically available as "Amberlite CG 50" ammonium form). The resin column was washed with water and eluted successively with aqueous ammonia (0.1 N 850 ml, 0.3 N 830 ml, 0.63 N 830 ml and 1 N 830 ml). The eluate was collected in 17 ml fractions. 320 ml of the fractions which were eluted by using 1 N aqueous ammonia and which showed high antibacterial activity to Bacillus subtilis PC 1219 and Escherichia coli JR 66/W 677 were combined together and concentrated to dryness to give 301.0 mg of a powder. This powder was rechromatographed again into a column of 11 ml of a cation-exchange resin made of a copolymer of methacrylic acid with divinylbenzene (commercially available as "Amberlite CG 50", ammonium form).
Thus, the resin column was at first washed with 40 ml of water and then with 90 ml of 0.5 N aqueous ammonia, and subsequently the elution was made using 0.75 N aqueous ammonia. Such fractions of the eluate were combined together to a total volume of 26 ml and concentrated to dryness to give 61.0 mg (yield 1.6%) of 1-N-[(S)-4-amino-2-hydroxybutyryl]DKB as a colorless crystalline powder, melting point 178°C (dec.).

brand name

Habekacin

Therapeutic Function

Antibiotic

Antimicrobial activity

The 1-N-(4-amino-2-hydroxybutyryl) derivative of dibekacin, to which it bears the same relation as amikacin bears to kanamycin A. Supplied as the sulfate.
Activity and stability to aminoglycoside-modifying enzymes are comparable with those of amikacin. It is active against many strains of methicillin-resistant Staph. aureus, either alone or in combination with β-lactam or other agents. Synergy with ampicillin has been observed for high-level gentamicin- and vancomycin-resistant enterococci.
A 3 mg/kg intravenous dose achieved a peak concentration of c. 8 mg/L after 1 h. The plasma half-life is about 2 h and protein binding 3–12%.
About 85% of the dose can be recovered from urine over 48 h. It is retained in renal failure, but moderately well removed by hemodialysis with a plasma half-life of 2–4 h. Peak concentrations of 10.9 mg/L and trough concentrations of 1.7 mg/L have been reported in patients treated for MRSA infection where C_max:MIC ratios of >25 and AUC:MIC ratios of >186 were associated with improved cure rates, and both Cmin and AUC were associated with the incidence of nephrotoxicity.
Toxicity and side effects are typical of the aminoglycoside class. It is used in severe infection cause by susceptible microorganisms, but is not widely available.