By C. Varek. Thomas Aquinas College, Santa Paula CA.

Penicillins with an Enlarged Spectrum A simple change in the side chain of penicillins leading to ampi- cillin (4-4) mediates a much higher activity against gram-negative bacteria purchase januvia 100mg with amex blood sugar issues, but at the cost of its activity against gram-positive cocci purchase 100mg januvia overnight delivery 4 week diabetic diet. The antibacterial spectrum of ampicillin has been moved toward the gram-negative side, which means that ampicillin cannot be called a broad-spectrum penicillin. Ampicillin is acid stable and shows a variable uptake from the gastrointestinal tract, which means that it can interfere with the normal composition of the mostly gram-negative commensal bacteria of the gut and cause enteritis symptoms. Another small change in the penicillin side chain, the addition of a hydroxyl group, results in amoxycillin (4-5), which is rapidly absorbed from the gastrointestinal tract almost completely, then without interfering with the normal bacterial composition in the colon. The pivampicillin (4-6)and bacampicillin (4-7) penicillin derivatives, which also have a good effect against gram-negative bacteria, were synthesized with the same goal of rapid and complete uptake from the gastrointesti- nal tract. The cell wall peptidoglycan can be regarded as a covalently bound giant molecule enclosing the cell. For the cell to be able to grow and divide, this armor must be plastic and be able to reorganize its structure. Bacterial cells affected by mecillinam show abnormal egglike structures when looked at under the microscope. Penicillins Stable to Penicillinases The most common form of bacterial resistance against betalac- tams is that the pathogenic bacterium produces a betalactamase, an enzyme cleaving the betalactam bond and thus inactivating the ability of the betalactam to interfere with the bacterial cell wall synthesis. The first observations of penillin inactivation by betalactamase, or penicillinase, as it was then called, were made in staphylococci at the end of the 1940s. The betalactamase hydrolyzes the betalactam bond of the penicillin with penicilloic acid (4-8) as a product. More than 90% of nosocomial Staphylo- coccus aureus isolates today are penicillin resistant because of an acquired betalactamase. The first derivative synthe- sized along these lines was methicillin (4-9), in its side chain carrying large and bulky methoxy groups, which were thought to reach over the betalactam bond to protect it. Methicillin did turn out to be a poor substrate for the staphylococcal penicilli- nase, which was found to degrade methicillin 30 times slower than it degraded penicillin G (benzylpenicillin). Methicillin has little effect on gram-negative bacteria and is acid labile, which means that it has to be administered parenterally. It turned out that dif- ferent betalactamases showed very different substrate spectra. The staphylococcal betalactamase simply does not recognize isoxazolyl penicillin as a substrate. Other betalactamases with different substrate profiles, which include isoxazolyl penicillin, were found later, however. So many betalactamases are now known that for all betalactams used clinically, one or several betalactamases have been found attacking it; that is, the sub- strate profiles of these enzymes are so varied that all known betalactams are included in them. Cloxacillin (4-11), dicloxacillin (4-12), and flukloxacillin (4-13) also belong to the isoxazolyl penicillins. They differ by carrying different chlorine and fluorine substitutions in the side chain which have been introduced for pharmacokinetic reasons. The antibacterial effect of this betalactam is too weak for clinical use as an antibacterial drug. It has, however, another property that makes it useful in the context of treating bacterial infec- tions with penicillins. When attacked by a betalactamase, its betalactam bond is hydrolyzed as with other betalactams, but this reaction leads to an irreversible inactivation of the enzyme. That is, the betalactamase commits suicide by exposing its active center to a covalent binding with the hydrolysis product of clavulanic acid. There are two other such suicide inhibitors, sulbactam and tazobactam, which are more similar to peni- cillin in that they have five-membered sulfur-containing rings attached to the betalactam structure. This inhibition phenomenon has been turned to advantage by combining clavulanic acid with a penicillin such as amoxycillin. The betalactamase inactivation by clavulanic acid protects the penicillin from enzymic degradation.

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