Antibacterial drug cephalosporins

Bacterial resistance can occur because of several mechanisms.28,76 Certain bacterial strains may be able to enzymatically destroy the antibacterial drug. The best example is the beta-lactamase enzyme that is found in bacteria that are resistant to beta-lactam drugs (penicillins and cephalosporins).54,86 As previously discussed, bacteria containing this enzyme can destroy certain penicillin and cephalosporin drugs, thus rendering the drug ineffective against these strains. 

Antibacterial drugs that affect cell wall synthesis include two large femilies,the penicillins and cephalosporins, and two individual drugs, bacitracin and vancomycin. 

Dual-acting antibacterial drugs linking quinolones (Fig. 16.35), such as ciprofloxacin, to cephalosporin... 

Antibacterial drugs that inhibit cell wall synthesis penicillins, cephalosporins and vancomycin... 

The outstanding success of penicillin, in both local and systemic bacterial infections, followed from its high selectivity, the reason for which is discussed in Section 13.1. The mammalian toxicity is so low that it has come to be regarded as the most innocuous of all antibacterial drugs (however, a small proportion of patients become sensitized to it). In 1948, Brotzu found (in a sewage outfall on the Sardinian coast) another mould, Cephalosporium, which gave rise to the related cephalosporin series of antibiotics (see Section 13.2). 

It is extremely important that fluoroquinolones have a specific mechanism of action, different from antibiotics and other groups of antibacterials (cephalosporins, aminoglycosides, etc.), which allows one to apply fluoroquinolones for treatment of infectious diseases caused by strains resistant to many other classes of antibacterials drugs. 

Fig. 5.4. Inactivation of /3-lactamases by cephalosporins (Fig. 5.1, Pathway b). The mechanism of this inactivation is similar to that of class-II inhibitors (Fig. 5.3, Pathway b) and is based on the slow hydrolysis of the acyl-enzyme complex (Pathway b). The normal deacylation of the acyl-enzyme complex represented by Pathway a results in the lost of antibacterial activity of the drug. The ratio between Pathways a and b is determined by the nature of the...

The quinolone antibiotics feature as the one main gronp of antibacterial agents that is totally synthetic, and not derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid more recent drugs in current use include ciprofloxacin, norfloxacin, and ofloxacin... 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

Two distinct approaches can be envisioned in the development of siderophore-drug conjugates. A strategy of drug delivery utilizing the pathogen s own iron-transport system to act as a delivery system has been referred to as the Trojan Horse approach. Examples in which sulfonamides 194 , penicillins, cephalosporins and other antibiotics attached to DFO which exhibit antibacterial activity were reported. 

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today s drugs to combat bacterial infections. Studies in (3-lactam chemistry were stimulated when (3-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic (3-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic (3-lactam antibiotics, e.g., thienamycin and carba-penems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. 

A primary problem in using penicillins, cephalosporins, and other beta-lactam antibiotics is that certain bacteria produce enzymes known as beta-lactamases.26,70 These beta-lactamase enzymes bind to the beta-lactam drug and destroy it before it can exert an antibacterial... 

Cephalosporin C (Figure 7.37) is produced commercially by fermentation using cultures of a high-yielding strain of Acremonium chrysogenum (formerly Cephalosporium acremonium). Initial studies of the antibiotic compounds synthesized by C. acremonium identified penicillin N (originally called cephalosporin N) as the major component, with small amounts of cephalosporin C. In contrast to the penicillins, cephalosporin C was stable under acidic conditions and also was not attacked by penicillinase ((5-lactamase). Antibacterial activity was rather low, however, and the antibiotic was poorly absorbed after oral administration. However, the structure offered considerable scope for side-chain modifications, more so than with the penicillins since it has two side-chains, and this has led to a wide variety of cephalosporin drugs, many of which are currently in clinical use. As with the penicillins, removal of the amide... 

---