Specific Antibacterial Agents

FIGURE 33-2 Folic acid metabolism in bacterial cells. Certain antibacterial drugs [e.g., sulfonamides and trimethoprim] inhibit the dihydrofolate synthetase and reductase enzymes, thus interfering with DNA biosynthesis. 

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For the purpose of this chapter, bacteria are categorized according to the criteria outlined in Table 33-1. This classification scheme does not fully identify all of the various characteristics of the many bacterial families. The classifications listed in Table 33-1 are used here only to categorize bacteria according to the use of antibacterial agents, which are discussed later in this chapter under Specific Antibacterial Agents. ... 

The initial clinical studies served as the first indication that Hansen s disease could be treated by means of a specific antibacterial agent. Up to then, leprosy had for centuries been regarded as incurable. 

Antimicrobial Activity. The elfamycins antimicrobial specificity and lack of toxicity in animals can be explained in view of species-dependent specificity of elfamycin binding to EE-Tu. Inefficient cellular uptake or the presence of a nonresponding EE-Tu were cited as responsible factors for the natural resistance in Halohacterium cutiruhrum (67), Lactobaci//us brevis (68), and in actinomycetes (5,69). The low activity of elfamycins against S. aureus was also attributed to an elfamycin-resistant EE-Tu system (70). However, cross-resistance with other antibacterial agents has not been observed (71). 

The inhibitors of RNA polymerase, which generates RNA from DNA, inhibit a crucial step in gene expression. Inhibition of the eukaryotic form of RNA polymerase is used in cancer chemotherapy and is also an important experimental tool. For example, actinomy-cin D binds to the guanine residues in DNA and blocks the movement of the eukaryotic RNA polymerase. Specific inhibitors of bacterial RNA polymerase can be used as antibacterial agents. Most of these inhibitors like rifamycin bind to the prokaryotic enzyme. 

Silver and mercury salts have a long history of use as antibacterial agents.241-243 The use of mercurochrome ((40), Figure 18) as a topical disinfectant is now discouraged. Silver sulfadiazene (38) finds use for treatment of severe burns the polymeric material slowly releases the antibacterial Ag+ ion. Silver nitrate is still used in many countries to prevent ophthalmic disease in newborn children.244 The mechanism of action of Ag and Hg is through slow release of the active metal ion—inhibition of thiol function in bacterial cell walls gives a rationale for the specificity of bacteriocidal action. 

Specific damage to bacteria is particularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells. Clearly this applies to inhibitors of cell wall synthesis, because human and animal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2). 

Mechanism of Action Clioquinol is a broad-spectrum antibacterial agent but the mechanism of action is unknown. Hydrocortisone is a corticosteroid that diffuses across cell membranes, forms complexes with specific receptors and further binds to DNA and stimulates transcription of mRNA (messenger RNA) and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the anti-inflammatory effects of corticosteroids applied topically to the skin Therapeutic Effect Alters membrane function and produces antibacterial activity Pharmacokinetics Clioquinol may be absorbed through the skin in sufficient amounts. 

Shah, S., et al. 1999. Evaluation of the factors influencing stomach-specific delivery of antibacterial agents for Helicobacter pylori infection. J Pharm Pharmacol 51 667. 

R Goldman, W Kohlbrenner, P Lartey, A Pernet. Antibacterial agents specifically inhibiting lipopolysaccharide synthesis. Nature 329 162-164, 1987. 

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