Tazobactam 3-lactamase inhibitory activity

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. 

The )3-lactamase inhibitory activity of some representative examples of the YTR class of compounds is shown in Table 6.10 [48, 83]. A comparison of the in vitro and in vivo activity of tazobactam with other inhibitors [Tables 6.11, 6.12, 6.14-6.18] shows that it has similar potency to clavulanic acid but is significantly inferior to BRL 42715 (31). 

The -lactamase inhibitory activity of BRL 42715, in comparison with clavulanic acid, sulbactam and tazobactam is shown in Table 6.14. It can be seen that BRL 42715 displays potent and progressive broad spectrum yff-lactamase inhibitory activity which represents a significant improvement over that of clavulanic acid, sulbactam and tazobactam. This was most noticeable with the chromosomal class I cephalosporinases, against which clavulanic acid is poorly active and sulbactam and tazobactam show only moderate activity. 

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-... 

Further, using a combination of X-ray crystallography and mass spectroscopy, Knox et al. [73] has firmly established a central role for Ser-130 in the inhibition of SHV-1 /1-lactamase (class A) by tazobactam. Many additional modifications (Table 3) were carried out on tazobactam with the aim of increasing inhibitory activity against AmpC enzymes, but none of these derivatives (e.g., 13c, 13d, and 13e) had any advantage over tazobactam [74— 77]. Renewed interest in the modification at the C-2 position of sulbactam was developed when scientists from Hoffmann-La Roche disclosed a series of 2/J-alkenyl penam sulfones that possess the ability to simultaneously inactivate both class A penicillinase as well as class C cephalosporinase. Compound... 

Over the past decade the essential goal in the modification of sulbactam or tazobactam has been to extend their activity towards the class C cephalosporinases. In spite of an enormous amount of effort, there has not been much success in achieving this goal. The penicillanic acid derivatives, as a class, show a good /3-lactamase inhibitory profile against class A... 

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