A lactam antibiotics

Abstract Resistance to modern antibiotics is currently a major health concern in treating infectious diseases. Abuse, overuse, and misuse of antibiotics in treating human illness have caused the pathogens to develop resistance through a process known as natural selection. The most common mechanism of resistance to -lactam antibiotics is the production of /3-lactamases, which destroy -lactam antibiotics before they reach the bacterial target. Over the last two decades, combination therapy involving treatment with a -lactam antibiotic and a /3-lactamase inhibitor has become very successful in controlling -lactamase-mediated bacterial resistance. Currently available inhibitors like... 

Penicillin V or phenoxymetliylpenicillin is a -lactam antibiotic produced by Penicillium notatum. It is a biosynthetic penicillin that should be differentiated from the semisynthetic penicillins since it is produced by altering the composition of the medium where the mold is growing. 

R.M. Morin and M. Gorman, (Eds.), Chemistry and Biology of a -lactam Antibiotics, Vol.l, Penicillins and Cephalosporins, Academic Press, New York, 1982... 

There are really two factors to be considered. First, the capability of a particular drug to cause the event which I just described, and secondly the capability of a drug administered to a person in which this process has taken place to be immediately recognized as antigenic and to elicit an anaphylactic reaction. A number of different chemical reactions have been associated with this phenomenon. One of them is simple acylation of protein by the / -lactam. Inasmuch as the mechanism of action of both the penicillins and cephalosporins is also thought to involve acylation by the -lactam, I think that it is very unlikely that there will ever be a -lactam antibiotic which is active and which will not in some patients form antigenic material by this same mechanism. It is my impression that cephalosporins have a lesser tendency to sensitize than some penicillins and that not all penicillin-sensitive people react to a given cephalosporin. The differences are probably quantitative and will never be qualitative. 

Volume 16/17 E. Tomlinson and A. Regosz, Antibiotics A -Lactam Antibiotics... 

Another example is the purification of a P-lactam antibiotic, where process-scale reversed-phase separations began to be used around 1983 when suitable, high pressure process-scale equipment became available. A reversed-phase microparticulate (55—105 p.m particle size) C g siUca column, with a mobile phase of aqueous methanol having 0.1 Af ammonium phosphate at pH 5.3, was able to fractionate out impurities not readily removed by hquid—hquid extraction (37). Optimization of the separation resulted in recovery of product at 93% purity and 95% yield. This type of separation differs markedly from protein purification in feed concentration ( i 50 200 g/L for cefonicid vs 1 to 10 g/L for protein), molecular weight of impurities (<5000 compared to 10,000—100,000 for proteins), and throughputs ( i l-2 mg/(g stationary phasemin) compared to 0.01—0.1 mg/(gmin) for proteins). 

Unit sales prices of from 800 to 900 fine chemicals are fisted weekly in the Chemical Marketing Reporter. This number reflects those fine chemicals produced and sold in industrial quantities. Some market studies on fine chemicals, fisting important product families, such as side chains for P-lactam antibiotics (qv). A/- and A-heterocycfic compounds, fluoroaromatics, etc, do exist (14,15). 

C QHyN O SNa, as a potentially useful P-lactamase inhibitor capable of potentiating the activity of a number of clinically important P-lactam antibiotics against resistant strains (153). 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

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). 

Sulbactam (25, R = R = H, R" = R " = dl ) is produced by Pfizer. The oral version of sulbactam in combination with ampicillin is called Unasyn Oral which is the mutual prodmg sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone [62893-19-0] called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any P-lactam antibiotic as Betamaze. In 1990 worldwide sales of sulbactam containing products were over 280 million. 

P-Lactam antibiotics exert their antibacterial effects via acylation of a serine residue at the active site of the bacterial transpeptidases. Critical to this mechanism of action is a reactive P-lactam ring having a proximate anionic charge that is necessary for positioning the ring within the substrate binding cleft (24). 

Studies on the mechanism of action of /3-lactam antibiotics have shed considerable light on how these agents kill bacteria. They also help explain qualitative differences between various agents and why there is a correlation between the reactivity of the /3-lactam and antibacterial activity. However, it is also clear that reactivity is only one factor in determining how effectively a given /3-lactam antibiotic will inactivate bacterial enzymes (82BJ(203)223). 

Compared to penicillins, cephalosporins are generally effective against a broader range of organisms and are more resistant to /3-lactamases. /3-Lactamases are bacterial enzymes that efficiently hydrolyze /3-lactam antibiotics to inactive species in which the /3-lactam bond has been cleaved. Cephalothin was the first cephalosporin to be marketed and continues... 

The most thoroughly studied mode of /3-lactam hydrolysis is that catalyzed by the enzyme /3-lactamase (EC 3.5.2.6). The elaboration of this enzyme is one of the three principal ways in which a bacterium can obtain resistance to a /3-lactam antibiotic (see Section 5.11.5.1), and much of the chemical work carried out on the penicillin molecule has been related to attempts to deal with this problem. A discussion of the /3-lactamases is beyond the scope of this work. The reader is referred to (B-79MI51101) for a recent review. 

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