Antimicrobial properties, penicillin

Tetracyclines are a family of antibiotics which display a characteristic 4-fused-core ring structure (Figure 1.16). They exhibit broad antimicrobial activity and induce their effect by inhibiting protein synthesis in sensitive microorganisms. Chlortetracycline was the first member of this family to be discovered (in 1948). Penicillin G and streptomycin were the only antibiotics in use at that time, and chlortetracycline was the first antibiotic employed therapeutically that retained its antimicrobial properties upon oral administration. Since then, a number of additional tetracyclines have been discovered (all produced by various strains of Streptomyces), and a variety of semi-synthetic derivatives have also been prepared (Table 1.18). 

Many advances in organic chemistry involve making and using derivatives of carboxylic acids. Proteins are bonded by amide functional groups, and chemists have created synthetic amides that emulate the desirable properties of proteins. For example, the nylon in a climbing rope is a synthetic polyamide that emulates the protein in a spider s web. All the penicillin and cephalosporin antibiotics are amides that extend the antimicrobial properties of naturally occurring antibiotics. 

The p-lactam ring confers the antimicrobial properties. However, the R group determines the degree of antibacterial activity, the pharmacological properties, including the types of bacteria against which it is active, and the degree of resistance to the P-lactamases exhibited by any particular penicillin antibiotic. These are the properties that must be modified to produce penicillins that are acid resistant, effective with a broad spectrum of bacteria, and 3-lactamase resistant. 

The use of higher plants and their preparations to treat infections is an age-old practice and in times past possibly the only method available. Interest in plants with antimicrobial properties has revived because of the current problems associated with the use of penicillin and other antibiotics. Therapy with several types of antibiotics is frequently accompanied by side effects and microbial resistance. It is currently accepted that the accumulation of secondary metabolites in plants can be a consequence of requirements for chemical defense against microorganisms. Research carried out in the chemical and biological sciences has resulted in much evidence concerning the defensive role of natural products. 

Penicillin, discovered in 1929 by Fleming, was first used therapeutically in 1941. The penicillin family of antibiotics, known as p-lactams, have been used extensively and successfully to treat bacterial infections, including Staphylococcus spp. The first reported bacterial resistance to p-lactams occurred in the 1940s, when extracts of bacteria were shown to neutralize the antimicrobial properties of penicillin. Soon after, strains of S. aureus were reported resistant to penicillin, in that they produced an enzyme capable of neutralizing penicillin called penicillinase (now termed P-lactamase). Currently, this form of resistance is common in as many as 93% of all S. aureus clinical isolates. Many coagulase-negative Staphylococcus spp. (CoNS) also produce P-lactamase and so are resistant to the penicillins as well [10]. 

The large number and diversity of available /3-lactams, mainly penicillins and cephalosporins, necessitate their classification. Penicillins can be classified primarily according to chemical structure. Table 5.2 shows that there is good correspondence between chemical structure and properties. The categorization of cephalosporins into chemically similar groups is not useful because their antimicrobial spectrum is not closely correlated with chemical structure, and classification into generations is based on their spectrum of microbial activity (Table 5.3). 

Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicillins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below. 

Parenteral preparations with antimicrobial activity, which depends on the causative pathogenic microorganism, and pharmacokinetic properties that meet most of these criteria include procaine penicillin G (aqueous suspension), amoxicillin trihydrate-clavulanate potassium combination (aqueous suspension), and enro-floxacin (solution). Enrofloxacin is not approved for use... 

The chemical nature and related physicochemical properties largely govern the distribution and elimination, which refers to biotransformation (metabolism) and excretion, of antimicrobial agents. The majority of antimicrobial agents are weak organic electrolytes, either weak acids (penicillins, cephalosporins, sulphonamides) or weak bases (aminoglycosides, lincosamides, macrolides, diaminopyrimidines, metronidazole), while fluoroquinolones, tetracyclines and rifampin are amphoteric compounds, and chloramphenicol and its... 

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