Penicillanic acids, lactamase inhibitors

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

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... 

Penicillanic acid derivatives are synthetically produced /3-lactamase inhibitors. 

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-... 

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. 

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. 

Enzymatic inactivation or modification of antibiotics has been discussed by many authors [179-182, 186-188], As described earlier, /(-lactams may be susceptible to /(-lactamases. During the past 30-odd years, several -lactams have been synthesized that are less susceptible to these enzymes. Such drugs include (i) newer types of /(-lactam structures, e.g. carbapenems (37), cephamycins (40) and carbacephems (53), and (ii) modifications of the side-chains of existing penams (38) or cephems (39) [317]. Nevertheless, the wide diversity of /(-lactamases [180,181,318] means that organisms producing enzymes with broad-spectrum activity may be able to resist some members of the /(-lactam group, /(-lactamase inhibitors such as clavulanic acid (36), and the penicillanic acid sulphone (54) derivatives, tazobactam (55) and sulbactam (56) have been combined with, and protect, appropriate /(-lactamase-susceptible penicillins, with useful clinical results. Most extended-spectrum /(-lactamases are susceptible to these inhibitors, but newer -lactamase inhibitors may still be needed. 

SEMI-SYNTHETIC yff-LACTAMASE INHIBITORS Clavulanic acid derivatives Penicillanic acid sulphone 6- -Halopenicillanic acid derivatives 6-Acetylmethylene penicillanic acid 6-Methoxymethylene penicillanic acid 6-Heterocyclylmethylene penam sulphones 2-y8-(Substituted methyl) penam sulphones 6-(Substituted methylene) penems... 

The first notable success was that of penicillanic acid sulphone (sulbactam CP-45,899) (23) [40], which was synthesized by Pfizer chemists from 6-APA (8) and shown to possess potent -lactamase inhibitory activity. Many other semi-synthetic yS-lactamase inhibitors have been... 

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. 

Penicillanic acid derivatives are synthetically produced P-lactamase inhibitors. Penicillanic acid sulphone (Fig. 10.6D) protects ampicillin from hydrolysis by staphylococcal P-lactamase and some, but not all, of the P-lactamases produced by Gram-negative bacteria, but is less potent than... 

The answer may be in discovering more specific mechanism-based P-lactamase inhibitors. It is curious that the best drugs developed so far are also P-lactam compounds (Fig. 6-14). One very interesting inhibitor is penicillanic acid sulfone (sulbactam, Fig. 6-14). This drug acts as a substrate (becomes hydrolyzed) and as an irreversible inactivator of TEM-type P-lactamase (covalently binding to it via molecular cleavage). 

Tazobactam is a penicillanic acid sulfone P-lactamase inhibitor. In common with the other available inhibitors, it has poor activity against the inducible chromosomal P-lactamases of Enterobacteriaceae, but has good activity against many of the plasmid P-lactamases, including some of the extended-spectrum class. It has been combined with piperacillin as a parenteral preparation (Zosyn). 

FIGURE 8.5 Structures of /3-lactamase inhibitors ciavulanic acid, penicillanic acid sulfone(s), carba-penem(s), 6/8-halopenam(s), and sulfenimine(s). 

This catalytic mechanism is consistent with data from X-ray crystallography, site-specific mutagenesis, and various biochemical studies. In crystal structures of E. coli TEM-1 )8-lactamase (34) and other related class A )8-lactamases (35—37), the side chains of the conserved residues (Ser-70, Lys-73, Ser-130, and Glu-166) are, together with a water molecule, clustered around the bound substrate (penicillin G). The presence of a methoxy or hydroxymethyl group on the a face of the j8-lactam ring, e.g., in cefoxitin or 6a-(hydroxymethyl)penicillanic acid, results in a displacement of the water (-712), thereby allowing the mechanism-based inhibitors to form rather stable acyl-enzyme intermediates (38). Substitution of either Lys-73 by Arg or of Ser-130 by Ala or Gly impairs the acylation step. Substitution of Glu-166 by Asn or Ala drastically reduces the deacylation step, leading to the accumulation of the acyl-enzyme intermediate (39,40). 

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