Activity, cephalosporin antibiotic

Cefpiramide (64) is a third generation cephalosporin with a l-methyl-[lH)-tetra2ol-5-ylthio-methyl moiety at C-3 and an acylated -hydroxyphenylglycine moiety at C-7. It includes in its activity spectrum reasonable potency in vitro against many strains of Pseudomonas. It can be synthesized in a variety of ways including condensation of cephalosporin antibiotic 63 with 6-methyl-4-(l-H)-pyridone-3-carboxylic acid in the form of its active N-hydroxysuccinimide ester (62) to produce cefpiramide (64) [20,21],... 

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

The mechanism of serine (3-lactamases is similar to that of a general serine hydrolase. Figure 8.14 illustrates the reaction of a serine (3-lac(amasc with another type of (3-lactam antibiotic, a cephalosporin. The active-site serine functions as an attacking nucleophile, forming a covalent bond between the serine side chain oxygen... 

Vancomycin and teicoplanin display excellent activity against staphylococci and streptococci, but because of the wide availability of equally effective and less toxic drugs, they are second-line drugs in the treatment of most infections. As antistaphylococcal agents they are less effective than 3-lactam cephalosporin antibiotics, such as nafciUin and cefazoUn. They have attained much wider use in recent years as a consequence of the emergence of methicUlin-resistant S. aureus (MRSA) infections, in particular the growing importance of Staphylococcus epidermidis infections associated with the use of intravascular catheters and in patients with peritonitis who are on continuous ambulatory peritoneal dialysis. 

Cephalosporins are -lactam antibiotics that block microbial cell wall synthesis. The original cephalosporin. Cephalosporin C, has only weak antibiotic activity. Therefore much more powerful second generation cephalosporins were developed by side-chain modification. Modifications at Cl are most effective but modifications at position 3 are also important so as to increase in vivo activity. Synthesis of the second generation cephalosporin cefuroxime requires the replacement of the C3 acetoxy side-chain of the precursor with a caibamate group. Chemical methods proceed via a hydroxylated intermediate which causes problems due to a tendency to lactonise at low pHs. Therefore development of a biocatalysis step was initiated in order to achieve selective reaction nnder mild conditions. 

Cefixime is an orally active third-generation cephalosporin antibiotic which has marked in-vitro bactericidal activity against a wide variety of gram positive and negative organisms. It is indicated for the treatment of urinary tract, infection, respiratory tract infection and biliary tract infection etc. 

An important group of four-membered heterocyclic compounds are the derivatives of the /i-lactam [azetidin-2-one (15)] system. Many of the compounds are biologically active, for example, the monocyclic nocardicins [e.g. (16)] and the bicyclic penicillin and cephalosporin antibiotics [e.g. (17) and (18) respectively], and the -lactamase inhibitors of the clavam group (19). 

The following section has two main objectives first, to summarize the classification of cephalosporins in terms of their spectrum of activity and second, to provide an overview of the new cephalosporin antibiotics discovered in the last decade. 

Adding different side chains extensively modified the parent cephalosporin compound and created a whole family of cephalosporin antibiotics. For the sake of convenience, these drugs are considered as first-, second-, third-, or fourth-generation componnds based on their spectra of bacterial activity and their clinical uses (Table 11-4). 

Aminocephalosporanic acid (15, Scheme 9) is an important intermediate in the production of many semisynthetic cephalosporin antibiotics (66, 67). However, direct deacylation of cephalosporin C (13) to 15 by cephalosporin C acy-lase is unfavorable, so an enzymatic process is used involving D-amino acid oxidase (DAAO) oxidation of 13 to A-glutaryl-7-aminocephalosporanic acid (14, GL-7-ACA) followed by deacylation to 15 and glutaric acid, catalyzed by GL-7-ACA acylase from Pseudomonas sp. 130 (Scheme 9) (68, 69). GL-7-ACA acylase underwent pseudo first-order time-dependent inactivation by 7 3-bromoacetyl aminocephalos-poranic acid (16) (70). Dialysis did not regenerate enzyme activity, indicating irreversible inhibition. The rate of inactivation was lowered by the presence of either glutaric acid or 15,... 

On the basis of the work of CIBA-Geigy A. G. and the Woodward Forschungsinstitut, the original total synthesis of cephalosporin has been extended with the incorporation of many fascinating details to the preparation of new derivatives [64-73]. Some features of this extensive work are shown in Scheme 8.2. Although an analysis of antibiotic activities toward different strains has not been published so far, it was found that (39) ( Cephalocillin ) and (40) are able to inhibit S. aureus, Proteus vulgaris and Bacillus megaterium [26]. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

The class A P-lactamases are a subset of the active-site serine P-lactamases. TEM-1 P-lactamase is a class A enzyme encoded by the ft/ajEM-l gene that is present on the transposons Tn2 and Tn3 (Datta et al, 1965). Epidemiological studies have shown that TEM-1 is the most common plasmid-mediated P-lactamase and is therefore a major determinant of bacterial resistance to P-lactam antibiotics (Wiedemann et al, 1989). Compounding the problem of resistance is the discovery that TEM-1 mutant variants with altered substrate specificity have been identified in natural isolates (Jacoby and Medieros, 1991). These variant enzymes contain from one to three amino acid substitutions that enable the enzyme to hydrolyze the newer extended-spectrum cephalosporin antibiotics such as cefotaxime and ceftazidime (Jacoby and Medieros, 1991). Thus, the selective pressure of antibiotic therapy le s to die creation of new enzymes with expanded hydrolytic capabilities. 

Tune B.The nephrotoxicity of cephalosporin antibiotics. Sturcture-activity relationship. Commun Toxicol 1993 1 145-157. Pearson PG, Omichinski JG, Flolme JA, McClanahan REI, Brunborg G, Soderlund EJ, Dybing E, Nelson SD Metabolic activation of tris (2,3, dibromopropyl) phosphate to reactive intermediates Covalent binding, reactive metabolite formation and differential metabolite-specific DNA damage, n v Vo.Toxicol AppI Pharmacol 1993 118 186-196. 

Tune BM.The nephrotoxicity of cephalosporin antibiotics-structure-activity relationships. Comm Toxicol 1986 1 (2) 145-170. Goldstein RS, Smith PFTarloff, JB, Contardi L, Rush GF, HookJB. Biochemical mechanisms of cephaloridine nephrotoxicity. Life Sell 988 42(19) 1809-1916. 

Hori R, Ishikawa Y,Takano M, OkanoT, Kitazawa S, Inui K.The interaction of cephalosporin antibiotics with renal cortex of rats accumulation to cortical slices and binding to purified plasma membranes. Biochem Pharmacol 1982 31(13) 2267-2272. McMurty RJ, Mitchell JR. Renal and hepatic necrosis after metabolic activation of 2-sustituted furans and thiophenes, including furosemide and cephaloridine.Toxicol AppI Pharmacol 1977 42 285-300. 

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