Of P-lactams

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

P-Lactamases are enzymes that hydrolyze the P-lactam ring of P-lactamantibiotics (penicillins, cephalosporins, monobactams and carbapenems). They are the most common cause of P-lactam resistance. Most enzymes use a serine residue in the active site that attacks the P-lactam-amid carbonyl group. The covalently formed acylester is then hydrolyzed to reactivate the P-lacta-mase and liberates the inactivated antibiotic. Metallo P-lactamases use Zn(II) bound water for hydrolysis of the P-lactam bond. P-Lactamases constitute a heterogeneous group of enzymes with differences in molecular structures, in substrate preferences and in the genetic localizations of the encoding gene (Table 1). 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

P-Lactamases (EC 3.5.2.6) produced by bacteria cleave the P-lactam ring and are responsible for their resistance to P-lactam antibiotics. Lactamases are useful catalysts for the enantioselective hydrolysis of P-lactams and other cyclic amides. P-lactams shown in Figure 6.40 were resolved by whole-cell systems containing an amidase [106]. 

Lipases are generally inactive on the amide bond. One notable exception is the hydrolysis and alcoholysis of P-lactams by CAL-B [108-112]. For example, CAL-B... 

Page Ml (ed) (1997) The chemistry of P-lactams. Chapman and Hall, London... 

Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T (2002) The development of the first catalyzed reaction of ketenes and imines catalytic, asymmetric synthesis of P-lactams. J Am Chem Soc 124 6626-6635... 

Hodous BL, Fu GC (2002) Enantioselective Staudinger synthesis of P-lactams catalyzed by a planar-chiral nucleophile. J Am Chem Soc 124 1578-1579... 

Discuss the importance of P-lactam allergy screening and how this could impact resistance and health care costs. 

PJ Sinko, GL Amidon. Characterization of the oral absorption of P-lactam antibiotics. I. Cephalosporins Determination of intrinsic membrane absorption parameters in the rat intestine in situ. Pharm Res 5 645-650, 1988. 

Bretschneider, B., Brandsch, M., Neubert, R., Intestinal transport of p-lactam antibiotics analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and transepifhelial flux, Pharm. Res. 1999, 16, 55—61. 

McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL Prevention of P-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995 90 439-448. 

Use of an interesting enamine photooxidation reaction has teen made of in the synthesis of P-lactams from 2-azetidine carboxylic esters (6.19) 625>. 

Several reviews of P-lactam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions , enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of p-lactams <99MI955>. 

Two groups of workers have studied the reaction of p-lactams with dimethyl titanocene to give 2-methyleneazetidines <00TL1975, 00TL5607>. Reduction of P-lactams with chloroalane gave azetidines in high yield <99JOC9596>. 

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