Antibiotics selective toxicity

Antibiotics are toxic water-solubie compounds produced by molds or bacteria which inhibit the growth of other microorganisms. For an antibiotic to be useful in medicine it should have a high order of selective toxicity to microorganisms which are pathogenic to man. Al-... 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

The origin of the success of fl-lactam antibiotics mainly results from the extreme low toxicity of these compounds with regard to human beings. In other words, P-lactam antibiotics have a highly selective toxicity for bacteria since they do not interfere with human metabolism, but inhibit the formation of the cell wall of growing bacteria. 

The phenomenon of bacterial resistance to antibiotics was already known by the pioneers of the era of antibiotics, like Paul Ehrlich, who coined the term selective toxicity as the basic principle of antimicrobial therapeutics, as well as Gerhard Domagk, the inventor of the sulfonamide drugs, and Sir Alexander Fleming, the discoverer of the penicillins. When penicillin G was introduced into clinical practice in 1944, as many as 5% of the isolates of Staphylococcus aureus were resistant to penicillin, while 5 years later the percentage was 50%. 

When tested, the antibiotic compounds killed or inhibited the growth of two varieties of E. coli but had no effect on several other types of cells. These results show that in response to bacterial infection the ants elaborated an antibiotic that was selectively toxic to the pathogen. Their defense was tailored closely to their need. It is too soon to know more, but it seems that looking for new antibiotics in ants is a promising idea. Further research should establish whether ant antibiotics will lead to drugs for human use and also reveal whether other crowded species also synthesize antibiotics. 

Macrolides, both erythromycin and others, inhibit the synthesis of bacterial proteins. The primary mechanisms of protein synthesis are identical in humans and bacteria. However, there is a significant difference that allows a specific antibiotic to exhibit selective toxicity with respect to bacteria. 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

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. 

Unfortunately, there are few pure examples of true selective toxicity. Perhaps the best is penicillin. The therapeutic specificity of this antibiotic is based upon the qualitative difference between bacterial cell wall synthesis and mammalian cell membrane synthesis. Synthesis of the former can be inhibited by penicillin while the latter is unaffected. Thus, penicillin is one of the few examples of a drug that can actually cure an illness. A similar example involves the sulfa drugs, which interfere with the synthesis of folic acid, used in nucleic acid formation, in bacteria. While bacteria must synthesize their own folic acid, mammalian cells utilize dietary, preformed folic acid and are not susceptible to interference with its formation. 

Microbes also have a plasma membrane that resides adjacent to their cell wall. Polymyxins are amphipathic agents (containing both nonpolar, lipophilic and polar, lipophobic groups) that interact with phospholipids in microbial cell membranes. The result is disruption of the membrane and increased permeability. However, because microbial and mammalian cell membranes are not exceedingly dissimilar, polymixins can produce significant toxicity in humans (i.e., they have low selective toxicity). This is also true for the related drug nystatin. This is why these particular antibiotics are not generally used systemically and are usually restricted to topical application. 

Selective toxicity to target organisms Since most antibiotics have selective toxicity to target organisms and low toxicity to mammals as shown in Table III, they can be safely used without harming man, livestock, fish and crops. Mode of action of agricultural antibiotics are summarized in Table XV. 

Antibiotics usually have a specific site or mode of action whereby they achieve a selective toxic effect against bacteria but not human host cells. In contrast, biocides frequently have multiple target sites in the bacterial cell and by their very nature are often toxic not only to bacteria and other micro-organisms but also to host cells [7,23,24], Thus, mutation at, or absence of, a normal target site (or the presence of an additional target site) may be responsible for producing resistance to antibiotics but not to biocides. 

Selective toxicity refers to differences in toxicity between two species simultaneously exposed. See Figure 9.26, where rats show a higher response than mice to a certain dose. This is the basis for the effectiveness of pesticides and drugs. For example, an insecticide is lethal to insects but relatively nontoxic to animals in the same vein, antibiotics are selectively toxic to microorganisms while virtually non-toxic to humans. 

It is interesting to note that an analog of myristic acid (14 0) showed selective toxicity to African Trypanosomes (77), PUFAs also can kill Helicobacter pylori (78), and the actions of some antibiotics could be potentiated by PUFAs (79), which lends support to the concept that PUFAs may function as endogenous anti-infective-like molecules (80, 81). 

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