Clavulanic acid, lactamase inhibitor

In addition to the enzyme inhibitors produced by fungi used to lower cholesterol (statins), several bacterial enzyme inhibitors have also been studied for potential utilization in medicine. The most important is clavulanic acid, the inhibitor of p-lactamases discussed above in the section Search for New Antibiotics in the Following Decades. ... 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important P-lactamases (10—14,57,58) including penases, and Richmond-Sykes types 11, 111, IV, V, VI ([Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), stmcture activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

Garbapenem P-Lactamase Inhibitors. Carbapenems are another class of natural product P-lactamase inhibitors discovered about the same time as clavulanic acid. Over forty naturally occurring carbapenems have been identified many are potent P-lactamase inhibitors. Garbapenem is the trivial name for the l-a2abicyclo[3.2.0]hept-2-ene ring system (21) shown in Table 3. The synthesis (74), biosynthesis (75), and P-lactamase inhibitory properties (13,14,66) of carbapenems have been reviewed. Carbapenems are often more potent than clavulanic acid and include type I Cephases in the spectmm of inhibition. Table 3 Hsts the available P-lactamase inhibition data. Synergy is frequendy difficult to demonstrate because the compounds are often potent antibacterials. 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

Although a broad range of P-lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid (12, R = CH2OH, R = H), manufactured by SmithKlinp Beecham, is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin [34787-01-4], C25H2gN20 S, has the trade name, Timentin. In 1990 worldwide sales of clavulanic acid containing products were about 725 million. 

Other examples of a-keto acid-dependent enzymes are mammalian proline hydroxylase and bacterial clavaminate synthase [113]. The latter enzyme is of particular interest as it is responsible for the catalysis of three individual steps in the biosynthesis of the (3-lactamase inhibitor clavulanic acid (Scheme 10.30). 

Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and clavams (/8-lactamase inhibitors). The metabolic engineering of penicillin and cephalosporins production has been summarized by several good reviews [71,72], so the focus here is clavulanic acid, which has attracted interest in recent years. 

The answer is d. (Hardman, pp 1097—1098.) The antibiotic clavu-lanic acid is a potent inhibitor of p-lactamases. The mode of inhibition is irreversible. Although clavulanic acid does not effectively inhibit the transpeptidase, it maybe used in conjunction with a p-lactamase-sensitive penicillin to potentiate its activity... 

Beginning in the late 1980s, three -lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) have been used against serine enzymes, usually in combination with penicillins more susceptible to /1-lactamase hydrolysis. This therapeutic strategy has been effective over two decades. The following section provides a brief overview on various classes of -lactam-based inhibitors. 

The real breakthrough in identifying a -lactamase inhibitor came in 1976 with the isolation of a bicyclic -lactam, called clavulanic acid la (Fig. 3), produced by a strain of Streptomyces clavuligerus [21,22], In itself, this bicyclic -lactam is a weak antibiotic, but a powerful inhibitor of most class A en-... 

After clavulanic acid, the penicillanic acid derivatives (particularly the corresponding sulfone analogs) have been the subject of intense research in the -lactamase inhibitor area. From this extensive investigation, two compounds (sulbactam and tazobactam) from this class have been successfully introduced into clinical use. The penicillanic acid sulfones are /3-laclamasc inhibitors that are quite homologous to clavulanate in both their mechanism of action and in the spectrum of -lactamases susceptible to their action. The first notable success in this field was the discovery of sulbactam 7 (Fig. 7), which was reported by Pfizer chemists in 1978 and shown to possess potent inhibitory activity, principally for class A //-lactamases. It had greater affinity for class C types than clavulanate. From careful comparison of its structure to clavulanate, a rational basis for the similarities between the two is apparent. Both lack a C-6 substituent. Since the absence (or presence) of this substituent is an important, but not exclusive, factor in //-lactamase recogni-... 

The first clinical application of the second strategy (to overcome bacterial resistance by neutralizing the /3-lactamases) was the combination of clav-ulanic acid (5.12) and amoxicillin. The efficacy of clavulanic acid has stimulated research on other inhibitors of /3-lactamases, leading to the discovery of a number of other inactivators such as sulbactam (5.13), 6/3-bromopenic-illanic acid (5.14), and olivanic acid (5.15) [44] [45],... 

Mechanistic investigations have shown that these compounds behave as suicide inhibitors (preferably called mechanism-based inactivators) in the sense that they are recognized by /3-lactamases as substrates, but the great stability of the acyl-enzyme intermediate blocks turnover of the enzyme [46] [47]. /3-Lactamase inhibitors can be divided into two classes, class I and class II class-I inhibitors (e.g., clavulanic acid (5.12)), in contrast to those of class II (e.g., olivanic acid (5.15)), have a heteroatom at position 1 that can lead to ring opening at C(5). The mechanistic consequences of this difference in structure are illustrated by the general scheme in Fig. 5.3. 

Combinations of /3-lactamase inhibitors with /3-lactam antibiotics are very useful in the treatment of infections, since they are relatively immune to the emergence of new resistance. However, a /3-lactamase resistant to inactivation by clavulanic acid has been identified [52],... 

Co-amoxiclav consists of the combination of amoxicillin (penicillin antibacterial agent) and clavulanic acid (beta-lactamase inhibitor) which is associated with a risk of crystalluria in patients with renal impairment who are receiving high doses, particularly during parenteral therapy. 

Co-amoxiclav is a combination of amoxicillin (the beta-lactam penicillin) and clavulanic acid, a beta-lactamase inhibitor. 

Clavulanic acid and sulbactam An addition of beta-lactamase inhibitors, such as clavu-lanic acid (32.1.1.35) and sulbactam (32.1.1.36) to penicillins or to aminopenicillins of a broad spectrum of action significantly expands their antimicrobial spectrum. 

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. Currently, a number of combined drugs containing various combinations of beta-lactamase antibiotics and inhibitors are used. 

In the search for structural diversity, and novel therapeutic agents, unique ring structures like the 1,2,5-thiadiazole have always captured the imagination of chemists. Often, as in the case of timolol (4), the interest is rewarded. In the early 1990s, a simple thiadiazole was appended to a penem in the development of the structure-activity relationships for a series of ) -lactamase inhibitors. The result was enhanced penetration of the bacterial membrane and a broader spectrum of activity versus clavulanic acid <9lJAN33l>. 

In combination with beta-lactamase inhibitors, like e.g. clavulanic acid, the aminopenicillins can be effective also against beta-lactamase-producing organisms. 

Beta-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. They are structurally related to the beta-lactam antibiotics however the antibacterial activity of these compounds is very weak or negligible. They are strong inhibitors of bacterial beta-lactamases and can protect beta-lactam antibiotics from hydrolysis by these enzymes. 

Obstetric infections can be treated with penicillin-beta-lactamase inhibitors such as amoxicillin-clavulanic acid, with extended spectrum penicillins (with or without beta-lacamase inhibitors if justified by local resistance surveillance data), with a first or second generation cephalosporin combined with metronidazole. In severe cases of streptococcal infection high doses of penicillin in combination with clindamycin is the treatment of choice. In amnionitis, maternal morbidity resolves with delivery. In endometritis, antibiotics should be stopped after the... 

Oral beta-lactam antibiotics such as amoxycillin, cotrimoxazole or doxycycline for 7-10 days are suitable for the treatment of bacterial sinusitis. Furuncles of the nose should be treated with an anti-staphyloccal drug for 5 days. Standard treatment for streptococcal pharyngitis consists of 10 days of penicillin. Malignant otitis externa responds to high dose quinolone therapy (e.g. ciprofloxacin 750 mg 2 t.d.) administered orally. For parapharyngeal abscess, high dose penicillin plus beta-lactamase inhibitors such as amoxycillin-clavulanic acid can be used. Duration of treatment is guided by clinical and parameters of inflammation, and abscesses often need several weeks to resolve by conservative treatment. 

Broad spectrum therapy is started on an empirical basis. Intra-abdominal infections can be treated by ampicillin (or amoxycillin) or clindamycin combined with aminoglycosides, penicillin-beta-lacta-mase inhibitors such as amoxycillin-clavulanic acid or a second or third generation cephalosporin combined with metronidazole are good alternatives. In patients with impaired immunity and/or prior use of antibiotics, i.e. when it is reasonable to expect resistant pathogens, a broad spectrum penicillin plus beta-lactamase inhibitor or a carbapenem can be used empirically in monotherapy. In septic patients, the rapidly bactericidal action of aminoglycosides is useful. Aminoglycosides should preferentially not be given for more than 3-5 days. 

Efforts to overcome the actions of the p-lactamases have led to the development of such p-lactamase inhibitors as clavulanic acid, sulbactam, and tazobactam. They are called suicide inhibitors because they permanently bind when they inactivate p-lactamases. Among the p-lactamase inhibitors, only clavulanic acid is available for oral use. Chemical inhibition of p-lactamases, however, is not a permanent solution to antibiotic resistance, since some p-lactamases are resistant to clavulanic acid, tazobactam, or sulbactam. Enzymes resistant to clavulanic acid include the cephalosporinases produced by Citrobacter spp., Enterobacter spp., and Pseudomonas aeruginosa. 

All mycobacteria produce (3-lactamase. In vitro, several (3-lactamase-resistant antibiotics or a combination of a (3-lactam with (3-lactamase inhibitors, such as clavulanic acid, are active against M tuberculosis and nontubercu-lous mycobacteria. However, the activity of (3-lactam agents against intracellular mycobacteria is generally poor. The (3-lactam agents may be useful in the treatment of MDR tuberculosis in combination with other antitubercular drugs but never as monotherapy. 

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