Chapter 52: General Principles of Antimicrobial Therapy

ABBREVIATIONS

ANTIMICROBIAL CHEMOTHERAPY: CLASSES AND ACTIONS

The germ theory of disease, based on the work of Louis Pasteur and Robert Koch, was a revolution in the human understanding of nature that linked specific microorganisms to specific diseases. The germ theory developed considerably in the 20th century, with identification and characterization of many microbial pathogens and their pathogenic mechanisms and the introduction of antimicrobial drugs. With the use of these drugs came issues of appropriate regimens, drug resistance, drug interactions, and toxicity.

This chapter reviews the general classes of antimicrobial drugs, their mechanisms of action, mechanisms of resistance, and patterns of kill by different classes of the drugs. Chapters 53 through 64 present the pharmacological properties and uses of individual classes of antimicrobials.

Microorganisms of medical importance fall into four categories: bacteria, viruses, fungi, and parasites. The first broad classification of antibiotics follows this classification closely, so that we have antibacterial, antiviral, antifungal, and antiparasitic agents. However, there are many antibiotics that work against more than one category of microbes, especially those that target evolutionarily conserved pathways. Within each of these major categories, drugs are further categorized by their biochemical properties.

Antimicrobial molecules should be viewed as ligands whose receptors are microbial proteins. The term pharmacophore, introduced by Ehrlich, defines that active chemical moiety of the drug that binds to the microbial receptor. The microbial proteins targeted by the antibiotic are essential components of biochemical reactions in the microbes, and interference with these physiological pathways kills the microorganisms. The biochemical processes commonly inhibited include cell wall synthesis in bacteria and fungi, cell membrane synthesis, synthesis of 30S and 50S ribosomal subunits, nucleic acid metabolism, function of topoisomerases, viral proteases, viral integrases, viral envelope entry/fusion proteins, folate synthesis in parasites, and parasitic chemical detoxification processes. Recently, antisense antibiotics have been developed; these work by inhibiting gene expression in bacteria in a sequence-specific manner. Furthermore, interferon-based products work by inducing specific antiviral activities of the infected human cells.

Classification of an antibiotic is based on the following:

• class and spectrum of microorganisms it kills

• biochemical pathway it interferes with

• chemical structure of its pharmacophore

Because ...