Bacterial pharmaceutical products

Abstract

Bacterial pharmaceutical products include antibiotics, antitumor agents, immunomodulators, and enzyme inhibitors. Other bioactive products of bacterial origin are coccidiostatic agents, nematicides, and insecticides. In addition, Escherichia coli, the prototype of molecular biology, is one of the most important hosts for the production of pharmaceutical recombinant proteins. The approach to antibiotic discovery, denoted as screening, proposed by Waksman in 1940, was so effective that by the end of the 1950s, members of all the main families of clinically useful antibiotics were discovered. In the following years, the screening concepts were refined, introducing methods to select organisms which were potential producers of novel antibiotics and orienting the screening toward biochemical targets rather than general activities. The approach was successful, and many interesting products were identified in the period of 1960-1980. In the following decades, the research was mainly driven by the need to stop the spread of antibiotic multiresistant strains due to the horizontal transmission of resistance genes. Some important success has been obtained, mainly by target-oriented modification of members of classical families of antibiotics. Most of the clinically effective antitumor agents were discovered in the 1960s by testing against tumor cell lines the active metabolites which were too toxic for use as anti-infective drugs. Only recently, a new family of products, active by stabilizing microtubulins, has been discovered by a target-oriented screening. Among the other bioactive metabolites, two products of Streptomyces have important clinical use as immunomodulators, and members of the avermectin family are largely used against nematode and arthropod infections. A family of exceptionally effective insecticides, the spinosins, receives an increasing share of the agricultural market. Most of the bacteria producing therapeutically effective antibiotics are actinomycetes, organisms belonging to the order Actinomycetales. Most of the products are produced by member of the genus Streptomyces. The genetics and biochemistry of antibiotic production has been mainly studied in strains of this genus. Antibiotics are products of the secondary metabolism, a form of cellular chemical differentiation linked in time, and sharing some initiator genes with cell morphological differentiation. The biosynthetic pathways yielding the backbone of most molecules of actinomycete pharmaceutical products consist of five different polymerization mechanisms: (1) and (2) the iterative polyketide synthases and modular polyketide synthases formed from small carboxylic acids units, polyaromatic compounds, and aliphatic chains; (3) the thiotemplate mechanism of polypeptide synthesis, by which most of the peptide antibiotics are produced; (4) the ribosome-dependent amino acid polymerization, which synthesizes the peptide lantibiotics; and (5) the condensation of carbohydrate units forming the aminosaccharide antibiotics. The genes governing the production of secondary metabolites are grouped in clusters, composed of structural genes encoding the enzymes catalyzing the synthesis of the molecule, and regulatory genes, determining the activation of the structural genes. During the growth phase of the Streptomyces life cycle, all the genes of the cluster are repressed. When the deprivation of an essential nutrient induces the onset of cell differentiation, a cascade of events activates the transcription of the regulatory genes, which in turn activate the genes governing the biosynthesis. Genetic studies have been essential in understanding the mechanisms of antibiotic synthesis regulation. Most relevant successes have been recently obtained by genetic engineering for the improvement of metabolite production, especially in orienting the production toward the preferred members of the metabolite complexes.