Antibacterial activities 3-lactamase inhibitors

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. 

Fig. 5.4. Inactivation of /3-lactamases by cephalosporins (Fig. 5.1, Pathway b). The mechanism of this inactivation is similar to that of class-II inhibitors (Fig. 5.3, Pathway b) and is based on the slow hydrolysis of the acyl-enzyme complex (Pathway b). The normal deacylation of the acyl-enzyme complex represented by Pathway a results in the lost of antibacterial activity of the drug. The ratio between Pathways a and b is determined by the nature of the...

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. 

Inhibitors of P-lactamase are known. The synthetic sulfone tazobactam (9.38), and clavulanic acid (9.39) both have weak antibacterial activity besides P-lactamase inhibitory activity, and they can be used in combination with vulnerable antibiotics. 

These substances resemble 3-lactam molecules (Figure 43-7) but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial 3 lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase inhibitors are most active against Ambler class A lactamases (plasmid-encoded transposable element [ ] lactamases in particular), such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and pneumoniae. They are not good inhibitors of class lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal 3 lactamases of bacteroides and moraxella. 

Sulbactam is a penicillanic acid sulfone. It exhibits a weak antibacterial activity, and is an inhibitor of -lactamases produced by some bacteria. Hence, it can enhance the activity of penicillins and cephalosporins against many resistant organisms when used in combination with diese antibiotics. Sulbactam, although it has a spectrum similar to that of clavulanic acid, is, however, a less potent inhibitor. 

Clavulanic Acid Class of fi-Lactamase Inhibitors. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important /8 lactamases, including penases and Richmond-Sykes types II, III, IV, V, VI (Bacteroides). 

Tricyclic-P-lactams Antibacterial and p-lactamase inhibitors Fig. 5 Biologically active tricyclic P-lactams... 

Bycroft et al. [83] have reported a series of semisynthetic penicillin derivatives such as, 6-spiro-epoxypenicillins F, G (Fig. 8) possessing both (3-lactamase inhibitory and antibacterial activity (Fig. 8). It has been found that novel chlorinated 6-spiro-epoxypenicillins F are potent in vitro inhibitors of a range of chemically important (3-lactamases [84], whereas, 6-spirocyclopropylpenems, G, show a reduced level of (3-lactamase inhibitory activity. The significance of the five fold difference between the turnover numbers for F(a) and G(b) (differ only in their stereochemistry at one center) was found to be in close comparison with the turnover number of 20,000, reported for the established (3-lactamase inhibitor, sulbactam [140]. Thus, the notable (3-lactamase inhibitory and antibacterial properties of these spiro-(3-1 actams depend upon the substituents and the stereochemistry of the epoxide. 

After the discovery of penicillins and cephalosporins as classical (3-lactam antibiotics and clinically useful active agents, the past few decades have witnessed a remarkable growth in the field of (3-lactam chemistry [1, 2]. The need for potentially effective (3-lactam antibiotics as well as more effective (3-lactamase inhibitors has motivated synthetic organic and medicinal chemists to design new functionalized 2-azetidinones. Besides their clinical use as antibacterial agents, these compounds have also been used as synthons in the preparation of various heterocyclic compounds of biological significance [3-7]. The potential use of some... 

The three inhibitors differ slightly with respect to pharmacology, stability, potency, and activity, but these differences are of little therapeutic significance. B-Lactamase inhibitors are available only in fixed combinations with specific penicillins. The antibacterial spectrum of the combination is determined by the companion penicillin, not the B-lactamase inhibitor. (The fixed combinations available in the USA are listed in the Preparations Available section.) An inhibitor will extend the spectrum of a penicillin provided that the inactivity of the penicillin is due to destruction by B... 

Recently, prodrugs have been constmcted in which amoxicillin (antibacterial agent) and clavulanic acid or cephalosporin 1-oxide (/3-lactamase inhibitors) are covalently linked. All these compounds show better antibacterial activity than Augmentin , comparable anti-/3-lactamase activity, and better solubility properties <2002BMC3489>. 

Clavulanic acid (80), isolated from Strepto-myces clavuligeruSy is similar in structure to the penicillins, except oxygen replaces sulfur in the five-membered ring (123). Clavulanic acid has weak antibacterial activity, but is a potent inhibitor of p-lactamases (124). A mixture of clavulanic acid and the j8-lactamase-sensitive amoxycillin was introduced in 1981 as Augmentin and has proved to be an effective combination to combat jS-lactamase-pro-ducing bacteria (125). In 2001,20 years after its launch, Augmentin is the best-selling antibacterial worldwide. 

Enzyme inhibitors such as cloxacillin and methicillin have been shown to potentiate the action of certain penicillins and cephalosporins against Ps. aeruginosa Figure 7.7). Thus, the presence of cloxacillin, which is a strong inhibitor of the inducible enzyme, potentiates the effect of cephaloridine which alone is susceptible to hydrolysis by the pseudomonas lactamase. Cloxacillin shows no antibacterial activity against... 

Like clavulanic acid, sulbactam possesses only weak antibacterial activity but displays synergistic activity in combination with many penicillins and cephalosporins. Comparative synergistic activity of sulbactam and other y5-lactamase inhibitors, in combination with ampicillin and amoxycillin, is presented in later sections. 

Because they cause prolonged inactivation of certain fi-lactamases. class I inhibitors ate particularly useful in combination with extended-spectrum, lactamase-sen.sitive penicillins to treat infections caused by lactamase-producing bacteria. Three such inhibitors, clavulanic acid, sulbactam, and tazobactam. are currently marketed in the United States for this purpose. A class II inhibitor, the carbapenem derivative imipenem. has potent antibacterial activity in addition to its ability to cause transient inhibition of some /3-lactamases. Certain antibacterial cephalosporins with a leaving group at the C-3 position can cause transient inhibition of lactamases by forming stabilized acylenzyme intermiediates. These are discu.ssed more fiilly below in this chapter. 

Tazobactam, USP. Tazobactam is a penicillanic acid sulfone that is similar in structure to sulbactam. It is a nioK potent /3-lactamase inhibitor than sulbactam and ha.- 3 slightly broader spectrum of activity than clavulanic acid. Ii has very weak antibacterial activity. Tazobactam is available in fixed-dose, injectable combinations with piperacillin, a broad-spectrum penicillin consisting of an 8 I ratio of pipci- acillin sodium to tazobactam sodium by weight and ma-keted under the trade name Zosyn. The pharmacokineticsprotein bound, experience ven little metabolism, and are excreted in active forms in the urine in high concentrations. 

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