Bacterial Pharmaceutical Products
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Bacterial Pharmaceutical Products ARNOLD L. DEMAIN AND GIANCARLO LANCINI
Introduction In contrast to plant metabolites, whose use against diseases has roots in folk and traditional medicine, bacterial pharmaceutical products are the result of large targeted research efforts, carried out by tens of laboratories all around the world. The original approach (later denoted “screening”) of Selman Waksman in 1939–1940 (Waksman and Woodruff, 1940) consisted of 1) systematically collecting soil microorganisms, 2) growing them in axenic culture, 3) testing the culture broths for their ability to inhibit the growth of pathogens, and 4) recovering the active substances produced. It was rapidly found that actinomycetes were most frequently positive; in particular, nearly 50% of Streptomyces strains isolated were active, mainly against Gram-positive bacteria. This widely applied approach was very fruitful by the early 1960s, and members of all the main families of clinically useful antibiotics were discovered. With the exception of the penicillins, cephalosporins and a few minor products, all were produced by actinomycetes. Their collective spectra of action covered practically all the important bacterial pathogens. In the 1960s, the need was felt for a substantial revision of the objectives and the methods of the screening. The number of antibiotics isolated was such that repetitions of discovery became more and more frequent. In fact, 1,300 metabolites had been reported in journals or patents by 1960, and over 2,000 by 1965 (data from Biosearch Italia database, courtesy of G. Toppo). General antibacterial activity appeared to be a less attractive target than activity against fungi, viruses or antibiotic-resistant bacterial strains. Antitumor efficacy was also considered as a possible target. Therefore, the search for novel metabolites was slowly changed in the various laboratories. Some devised methods for mass screening of unusual genera of microorganisms (such as rare actinomycetes) or organisms living in different (e.g., marine) environments. Others relied upon the use of new targets, rather than on isolation of novel producers, to select new products. The
result was the discovery of novel and important antimicrobial agents, antitumor substances and inhibitors of mammalian enzymes of potential pharmaceutical interest. Mammalian enzymes have been especially targeted in recent years, with the isolation of pharmacologically active metabolites and of antimicrobial agents occurring at present at about the same frequency. However, the number of new products of proven clinical value has been unfortunately declining. All these natural products are known as secondary metabolites (“idiolites”). They are low molecular weight products of microbial metabolism (such as antibiotics, pheromones, sex hormones, etc.) that differ from primary metabolites (amino acids, vitamins, purines, pyrimidines, etc.) in that they are not involved in growth processes but rather in mechanisms of su
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