58001-44-8 Usage
Description
Clavulanic acid is a potent antibiotic derived from the Streptomyces clavuligerus mold. It possesses weak intrinsic antibacterial properties but is an exceptional irreversible inhibitor of most β-lactamases. Clavulanic acid functions as a suicide inhibitor by acylating the active site serine, mimicking the normal substrate and leading to the inhibition of the enzyme. Its addition to ampicillin and amoxicillin preparations significantly enhances their potency against β-lactamase-producing strains.
Uses
Used in Pharmaceutical Industry:
Clavulanic acid is used as a beta-lactamase inhibitor for enhancing the effectiveness of antibiotics like ampicillin and amoxicillin against β-lactamase-producing bacteria. By inhibiting the enzyme responsible for antibiotic resistance, clavulanic acid allows the primary antibiotic to function more effectively, overcoming resistance and improving treatment outcomes.
Used in Research and Development:
Clavulanic acid is also utilized in the research and development of new antibiotics and pharmaceutical compounds. Its unique mechanism of action as a suicide inhibitor provides valuable insights into the development of novel drugs targeting bacterial resistance and other enzyme-related diseases.
Originator
Augmentin,Beecham,UK,1981
Manufacturing Process
100 ml of sterile water was added to a sporing culture which had been grown
on Bennetts agar in a Roux bottle for 10 days at 26°C. A mycelium/sporesuspension was produced and used to inoculate 75 liters of steam sterilized
medium of the following composition in tap water.Arkasoy is soybean flour supplied by British Arkady Co., Old Trafford,
Manchester, UK
The pH of the medium was adjusted to 7.0
The medium was contained in a 100 liter stainless steel baffled fermenter,
agitated by a 7.5 inch vaned disc impeller at 140 rpm. Sterile air was supplied
at 75 liters per minute and the tank incubated for 72 hours at 26°C.
The contents of the seed fermenter were used to inoculate 1,500 liters of
steam sterilized medium of the following composition in tap water.10% Pluronic L81 in soybean oil 0.2% V/V
The pH of the medium was adjusted to 7.0
The medium was contained in a 2,000 liter stainless steel fully baffled
fermenter agitated by two 19 inch vaned disc impellers at 106 rpm.
Sterile air was supplied at 1,200 liters per minute. Antifoam was added in 25
ml amounts as required. (10% Pluronic L81 in soybean oil). The fermentation
was controlled at 26°C until a maximum yield of clavulanic acid was obtained
between 3-5 days when 200-300 μg/ml of clavulanic acid were produced.
Therapeutic Function
Antibacterial
World Health Organization (WHO)
The amoxicillin/clavulanic acid combination should be reserved
for infections likely or known to be caused by amoxicillin- resistant beta-lactamase
producing strains. Amoxicillin/clavulanic acid is listed in the WHO Model List of
Essential Drugs.
Antimicrobial activity
It exhibits broad-spectrum but low intrinsic activity, most
MICs being in the range 16–128 mg/L. Enterobacteriaceae
and Staph. aureus are among the more sensitive and Ps. aeruginosa
the most resistant organisms. MICs of 8 mg/L against
H. influenzae and 0.1–4 mg/L for penicillinase-producing
N. gonorrhoeae are notable.
Pharmacokinetics
It exhibits broad-spectrum but low intrinsic activity, most
MICs being in the range 16–128 mg/L. Enterobacteriaceae
and Staph. aureus are among the more sensitive and Ps. aeruginosa
the most resistant organisms. MICs of 8 mg/L against
H. influenzae and 0.1–4 mg/L for penicillinase-producing
N. gonorrhoeae are notable.
Clinical Use
Clavulanic acid is an antibiotic isolated from Streptomycesclavuligeris. Structurally, it is a 1-oxopenam lacking the6-acylamino side chain of penicillins but possessing a 2-hydroxyethylidene moiety at C-2. Clavulanic acid exhibitsvery weak antibacterial activity, comparable with that of6-APA and, therefore, is not useful as an antibiotic. Itis, however, a potent inhibitor of S. aureus β-lactamaseand plasmid-mediated β-lactamases elaborated by Gramnegativebacilli.Combinations of amoxicillin and the potassium saltof clavulanic acid are available (Augmentin) in variousfixed-dose oral dosage forms intended for the treatment ofskin, respiratory, ear, and urinary tract infections causedby -lactamase–producing bacterial strains. These combinationsare effective against β-lactamase–producingstrains of S. aureus, E. coli, K. pneumoniae, Enterobacter,H. influenzae, Moraxella catarrhalis, and Haemophilusducreyi, which are resistant to amoxicillin alone. The oral bioavailability of amoxicillin and potassium clavulanate issimilar. Clavulanic acid is acid-stable. It cannot undergo penicillanicacid formation because it lacks an amide side chain.Potassium clavulanate and the extended-spectrum penicillinticarcillin have been combined in a fixed-dose, injectableform for the control of serious infections caused byβ-lactamase–producing bacterial strains. This combinationhas been recommended for septicemia, lower respiratory tractinfections, and urinary tract infections caused by β-lactamase–producing Klebsiella spp., E. coli, P. aeruginosa,and other Pseudomonas spp., Citrobacter spp., Enterobacterspp., S. marcescens, and S. aureus. It also is used in bone andjoint infections caused by these organisms. The combinationcontains 3 g of ticarcillin disodium and 100 mg of potassiumclavulanate in a sterile powder for injection (Timentin).
Synthesis
Clavulanic acid is isolated from Streptomyces clavuligerus [60–66], and sulbactam, a
sulfone of penicillanic acid, is synthesized from 6-APA [67–69]. Both compounds have
extremely weak antibacterial properties and act by forming irreversible complexes
with beta-lactamase, which inactivates the enzyme, and as a result the beta-lactam
antibiotic has time to destroy the microorganism.
Check Digit Verification of cas no
The CAS Registry Mumber 58001-44-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 5,8,0,0 and 1 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 58001-44:
(7*5)+(6*8)+(5*0)+(4*0)+(3*1)+(2*4)+(1*4)=98
98 % 10 = 8
So 58001-44-8 is a valid CAS Registry Number.
InChI:InChI=1/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-
58001-44-8Relevant articles and documents
Evidence that the Immediate Biosynthetic Precursor of Clavulanic Acid is its N-aldehyde Analogue
Nicholson, Neville H.,Baggaley, Keith H.,Cassels, Robert,Davison, Mark,Elson, Stephen W.,et al.
, p. 1281 - 1282 (1994)
(3R,5R) Clavulanate-9-aldehyde 1 has been detected in Streptomyces clavuligerus and an NADPH dependent dehydrogenase capable of reducing 1 to clavulanic acid 2 has been isolated from this organism.
Clavulanic acid aldehyde, beta-lactamase inhibitor
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Page 6, (2008/06/13)
A compound of formula (I): wherein R = H or Na, or a salt thereof and an enzyme, obtainable from Streptomyces species, having clavulanic acid dehydrogenase activity which is capable of converting (I) into clavulanic acid .
Process for the preparation of potassium clavulanate
-
, (2008/06/13)
A process for preparation of potassium clavulanate by the direct precipitation of clavulanic acid as the potassium salt by providing a solution of clavulanic acid in an organic solvent and mixing a potassium salt with this solution, with between 0.1 % v:v and 7.5 % v:v of water present in the region where the clavulanic acid and potassium salt contact, then isolating the so-formed potassium clavulanate.
Process for the preparation of clavulanic acid
-
, (2008/06/13)
A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with an amine of formula (II) where R1 is a group of general formula where R4 and R5 are independently hydrogen, alkyl, amino-substituted alkyl or substituted amino-substituted alkyl, and R2 and R3 are independently selected from hydrogen, alkyl, amino- or hydroxy-substituted alkyl or substituted amino-substituted alkyl, and m is zero or an integer 1 to 5; ii) isolating the amine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.
