BIOTECHNOLOGY - V. H. Gerasymenko - 2006

Part II. Specialized Biotechnologies

CHAPTER 11. BIOTECHNOLOGY OF ANTIBIOTIC PRODUCTION

The Discovery of the main groups of Antibiotics and the extensive complex of genetic and biochemical studies of their producers in the 1940s and 1950s—which enabled the large-scale production of fundamentally new medicinal drugs—can be ranked among The most significant achievements of biotechnology.

The demographic explosion in some countries and the dramatic increase in life expectancy in others were, at that time, largely driven by antibiotics. Among the products of the pharmaceutical industry in developed countries, antibiotics consistently rank first across all metrics.

Despite our understanding of The Structure of virtually all known substances with antibiotic activity, their chemical synthesis remains cumbersome and inefficient. In industrial settings, antibiotics for medical or veterinary use are obtained by exploiting the capacity of specific producer strains to synthesize a given antibiotic within a specific growth phase and under a predefined cultivation regime.

Antibiotics are low-molecular-weight substances that vary considerably in chemical structure. What these compounds share in common is that, while serving as metabolic products of microorganisms, they inhibit Microbial growth at very low concentrations. Most antibiotics belong to secondary metabolites, the so-called idiolites.

Microorganisms that produce secondary metabolites initially go through a period of rapid growth—the trophophase—during which the Synthesis of Secondary metabolites is negligible. As growth slows down or ceases due to the depletion of one or more essential nutrients in the culture medium, the microorganisms enter the idiophase. During this period, idiolites (antibiotics) are synthesized. While most microorganisms are sensitive to their own antibiotics during the trophophase, they lose this susceptibility in the idiophase. To protect antibiotic-producing microorganisms from self-destruction, it is necessary to rapidly reach the idiophase and subsequently cultivate the microorganisms within this phase.

To date, approximately 6,000 naturally occurring antibiotics and antibiotic substances are known, primarily produced by six genera of filamentous Fungi, three genera of actinomycetes (accounting for nearly 4,000 different antibiotics), and two genera of true Bacteria (nearly 500 antibiotics).

Among filamentous fungi, Molds of the genera Cephalosporium and Penicillium are producers of the so-called β-lactam antibiotics—Penicillins and Cephalosporins. The majority of antibiotic substances synthesized by actinomycetes, including Tetracyclines, belong to the genus Streptomyces (the single species Streptomyces griseus alone synthesizes over fifty antibiotics).

In addition to penicillins and cephalosporins, β-lactam antibiotics include cephamycins, which are produced by filamentous actinomycete bacteria belonging to the genus Streptomyces.

In 1945, Brotzu from the Institute of Hygiene in Cagliari (Sardinia) isolated the mold Cephalosporium acremonium from a seawater sample; this mold synthesizes several antibiotics, including cephalosporin C, which is particularly effective against penicillin-resistant Gram-positive bacteria.

Between the 1940s and 1970s, the number of newly discovered antibiotics grew linearly, with roughly 200 new compounds discovered each year. By the late 1970s, antibiotics were being identified at a rate of 300 compounds per year, 150 of which were produced by actinomycetes (Albert Sasson, 1987).

Out of the 5,000–6,000 natural antibiotics and antibiotic substances known today, only 100 are manufactured for commercial use, the majority of which (69) are derived from streptomycetes. The most important therapeutic antibiotics used until recently and at present belong to the following classes (Table 11.1).

The list of these antibiotic classes expands every year. This intense focus on discovering novel antibiotics is driven by the toxicity of existing drugs, allergic reactions to their administration, the increasing resistance of pathogenic microorganisms to them, as well as the constant need to combat pathogens against which currently known drugs are insufficiently effective.

Class="center">Table 11.1.

Major therapeutic antibiotics (after N. S. Egorov, 1987)

Global antibiotic sales in 1978 reached $4.2 billion. Of this total, $1.5 billion accounted for β-lactam antibiotics (penicillins and cephalosporins) and $1 billion for antibiotics synthesized by actinomycetes. In 1980, worldwide antibiotic production was approximately 25,000 tons, comprising 17,000 tons of penicillins, 5,000 tons of tetracyclines, 1,200 tons of cephalosporins, and 800 tons of erythromycins.

Since the mid-1960s, due to the increasing difficulty of isolating effective antibiotics and the widespread development of resistance to commonly used antibiotics among numerous pathogenic bacteria, researchers shifted their focus from discovering new drugs to modifying the structure of already existing ones. Their goal was to enhance antibiotic efficacy, protect them against inactivation by resistant bacterial Enzymes, and improve the pharmacological Properties of the drugs. Most research centered on penicillins and cephalosporins, whose structures incorporate a four-membered β-lactam ring consisting of three carbon atoms and one nitrogen atom: , making them amenable to chemical modification.