Antibiotics, lactam stability

Both the cephalosporins and the penicillins owe their antibacterial action to their ability to block bacterial cell-wall biosynthesis. Cephalosporin C is less active than the penicillins, but is less susceptible to enzymatic destruction by /3-lactamases, which are enzymes that cleave the lactam ring. In fact, the so-called resistance of staph bacteria to penicillins is attributed to the propagation of strains that produce /3-lactamase. Numerous semisynthetic penicillins and cephalosporins have been made in the hope of finding new broad-spectrum antibiotics with high activity but with greater /3-lactam stability. Several of these are in clinical use. 

A. Tsuji, E. Nakashima, K. Nishide, Y. Deguchi, S. Hamano, and T. Yamana, Physicochemical properties of amphoteric p-lactam antibiotics. III. Stability, solubility, and dissolution behavior of cefatrizine and cefadroxil as a function of pH, ( hem. Pharm. Bull. 31, 4057-4069 (1983). 

Compound 6c, also known as Sanfetrinem combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to p-lactamases, the bacterial enzymes that hydrolyze p-lactam antibiotics, and stability to dehydropeptidases. 

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). 

MJ Pikal, AL Lukes, JE Lang, K. Gaines. Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry Correlations with stability. J Pharm Sci 67(6) 767-773, 1978. 

Transition metal ions cause a dramatic increase in the rate of hydrolysis of /Madam antibiotics [75][133][134], For example, copper(II) and zinc(II) ions increase the rate of alkaline hydrolysis ca. 108-fold and 104-fold, respectively [76], It has been suggested that the metal ion coordinates with both the carboxylate group and the /3-lactam N-atom of penicillins (A, Fig. 5.20). This complex stabilizes the tetrahedral intermediate and, thus, facilitates cleavage of the C-N bond catalyzed by the HO ion [74] [75], Such a model appears applicable also to clavulanic acid, imipenem, and monobactams, but it re-... 

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

H. Mikami, M. Ogashiwa, Y. Saino, M. Inoue, S. Mitsuhashi, Comperative Stability of Newly Introduced /3-Lactam Antibiotics to Renal Dipeptidase , Antimicrob. Agents Chemother. 1982, 22, 693-695. 

A major stability problem in penicillins is the hydrolysis of the lactam ring as shown in Figure 3.14. Penicillins with an open lactam ring are inactive as antibiotics since it is the reactive lactam ring which kills the bacteria. 

It is formed by acylases that cleave off the side chain of the penicillins, and can also be obtained by the selective chemical cleavage of the amide, leaving the lactam intact. After this, 6-APA can be easily acylated by any carboxylic acid, and this has yielded literally thousands of semisynthetic penicillins in the past 30 years, many showing improved stability and activity. Some of them are lactamase resistant (methicillin (9.41), oxacillin (9.42) and its halogenated derivatives), whereas others are broad-spectrum antibiotics, like the orally active ampicillin (9.43), which also inhibits Gramnegative bacteria but is sensitive to lactamase. Carbenicillin (9.44) is particularly active against Pseudomonas and Proteus infections, which are unaffected by natural penicillins. Piperacillin (9.45), a broad-spectrum compound, is spectacularly active against Pseudomonas. 

Pikal, M. J., Lukes, A. L., Lang, J. E., and Gaines, K. (1978), Quantitative crystalhne determinations for b-lactam antibiotics by solution calorimetry Correlation with stability, /. Pharm. Sci., 67,767-773. 

The stability of several -lactam antibiotic in aqueous solutions is pH dependent. Optimum stability for monobasic penicillins in general is exhibited at pH 6-7, while for the amphoteric penicillins this coincides with the isoelectric point (18). A fast degradation occurs at both acidic and basic conditions. At pH 2.6, acid-labile -lactams such as penicillin G, methicillin, and nafcillin disappear almost completely while acid-resistant compounds like penicillin V and isoxazolyl penicillins survive (19). 

The thermal stability of oxytetracycline in liquid media, as indexed by the antimicrobial activity retained following heating at 71 C, has been shown to be much less than that of other antibiotics such as aminoglycosides and -lactams (71, 72). Recent investigation on the thermostability of oxytetracycline in water and vegetable oil showed that the drug is unstable in water at 100 C with a half-life of 2 min, but more stable in oil at 180 C with a half-life of 8 min. 

Much of the chemical reactivity of the /8-lactam antibiotics is associated with die /i-lactam moiety. The geometry and the accompanying increased ring strain results hr very little, if any. amide-resonance stabilization leading to a marked increase in chemical reactivity when compared to a normal amide. In fact, in many instances the reactivity of the lactam carbonyl is... 

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