Cephalosporins selective toxicity

The clinical effectiveness of the cephalosporins depends on a number of properties. The antibiotic must inhibit, or preferably kill, bacteria at acceptable concentrations of the drug (in vitro activity) it must be capable of achieving host serum and tissue levels greater than those required to inhibit the pathogenic organism and the selective toxicity profile must allow for safe administration to the host. 

Penicillins, cephalosporins, tetracyclines, acrinomvdns These are examples of classes of antibiotics each from a microorganism producing c) otoxic agents. The first three classes are selectively c) otoxic to bacteria, and the fourth cytotoxic to mammalian cancer cells, unfortunately with poor selective toxicity. The penicillins and cephalosporins inhibit bacterial cell wall synthesis, and tetracyclines selectively block protein synthesis at the bacterial ribosome. The actinomycins intercalate in a relative nonselective manner the... 

Some natural antibiotics contain a siderophore structure, for instance, 5i-albomycin 35, which is produced by Streptomyces subtropicus. The linear tripeptide portion chelates Fe(III) and, thereby, is able to utilize the iron-transport system of a range of microorganisms. Subsequent to uptake, peptidases localized in the cytoplasmic membrane hydrolytically release the toxic thioribosyl moiety. In principle, this property can be used for selective drug delivery. Preliminary studies indicated that substantial modification of the siderophore framework can be tolerated by microbial iron-transport systems. Surprisingly, simple modifications can be made to cephalosporin molecules, which endow them with the ability to interact with microorganism iron-transport mechanisms. Thus, simple incorporation of a catechol moiety, as in 36, endows this molecule with enhanced activity against Pseudomonas aeruginosa when compared... 

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). 

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