Francesco Parenti

Resistance of Microorganisms to Antibiotics

This chapter is composed of three independent but integrated parts. In the first one we describe the modifications present in the resistant bacterial cell with respect to the corresponding susceptible bacterial cell. This topic is closely correlated to the chapter on mechanism of action. In the second part we describe the possible localizations and modes of transmission of the genetic determinants of resistance. The approach applied is a systematic presentation of the different types of resistance mechanisms.

Activity of the Antibiotics

The activity of an antibiotic is defined and measured in terms of its capacity to inhibit microbial growth (bacteria, fungi, protozoa). Although the concept of growth is familiar as applied to macroscopic organisms (irreversible increase in volume as a function of time), it must be redefined to take into account microscopic organisms, because in this case two different levels of growth can be distinguished: population growth and growth of a single cell. By population growth we mean the increase with time of the number of microorganisms, i.e., the increase in the density of the microbial population. By cell growth we mean the synthesis of cellular material needed for one cell to give rise to two daughter cells. Obviously, the growth of the microbial population is the result of cell growth.

The Antibiotics: An Overview

Antibiotics are low molecular weight microbial metabolites that at low concentrations inhibit the growth of other microorganisms. The term low molecular weight substances refers to molecules of at most a few thousand daltons. We do not include among the antibiotics those enzymes, such as lysozyme, and other complex protein molecules that also have antibacterial properties. If the definition were to be adhered to rigorously, the only substances to be considered antibiotics would be the natural products of microorganisms. However, we now include in the category the following semisynthetic antibiotic substances: 1. products obtained by chemical modification of natural antibiotics or of other products of microbial metabolism; 2. products obtained by microbiological transformation of synthetic compounds.

Activities of the Antibiotics in Relation to Their Structures

This chapter describes the principal classes of antibiotics and attempts to demonstrate the relationships that exist between their chemical structures and their biological properties, especially their antibacterial activities, mechanisms of resistance, and toxicological profile. Knowledge of these relationships provides the basis for a rational search for new derivatives. Chemical modification of the antibiotics is a method for translating information obtained in this type of study into practical use, resulting in development of new products with more effective therapeutic properties.

Biosynthesis of Antibiotics

In terms of biogenesis, antibiotics are considered secondary metabolites. Secondary metabolites are natural products of low molecular weight with the following characteristics: 1. They are synthesized by only some microbial species. 2. They have no obvious function in the growth of the cell and are often produced after the culture has ceased to grow. 3. Cells able to make these molecules easily lose through mutation the capacity to synthesize them. 4. They often are made in families of similar products.

Mechanism of Action of the Antibiotics

An antibiotic inhibits growth of a microbial population. Population growth results from reproduction of individual cells, that is, from duplication of cellular material and subsequent division of the cell into two daughter cells. For an antibiotic to affect a microbial cell, it must (1) enter the cell, (2) bind physically to a cellular structure involved in some process essential for maintenance of the life or the growth of the cell, and (3) completely inhibit the process in which that structure is involved.