Tetracyclines discovery

The discovery and production of antibiotics has been of tremendous importance to human and animal health care. Prior to their discovery about half a century ago, many bacterial infections caused debilitating diseases and fatalities were high. The discovery of antibiotics was a major step in the treatment of infectious diseases, especially those caused by bacteria. Today about 50,000 tonnes of antibiotics are produced annually. About a third of this consists of penicillins, whilst tetracyclines make up about a quarter of the market. 

Discovery of Kanamycin, and Establishment oflMC. Chloramphenicol, chlor- and oxy-tetracyclines, and pyridomycin (H. Umezawa, 1967) were active, in in vitro experiments, against strains of tuberculosis, but these drugs, in contrast to streptomycin, were clinically inactive. H. Umezawa... 

The discovery of a novel structural class of antibacterials is notable, as these are few and far between. The sulfa drugs, p-lactams, quinohnes, tetracyclines, macrohdes, and aminoglycosides have been around for decades. Multiple improvements have been made over time in each of these classes but without breaking out into new structural classes. There are two notable, recent examples of new stractural classes of antibacterials and these are worth knowing about. 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Tetracyclines have been marketed since 1984, and, since discovery, some first-generation tetracyclines such as tetracycline, oxytetracycline, and chlorotetracychne have been extensively used in livestock and aquaculture, besides clinical use by humans. For human use, the second-generation tetracyclines doxycycline and minocycline have been prescribed to a great extent, and indeed prescription of the latter has steadily increased in the United States over the 2003-2005 period (Fig. 1.7). However, each of these tetracyclines is less than 0.5% of all the other 200 most prescribed dmgs. Tetracyclines are also prescribed to a good extent in several European countries (Fig. 1.6), with the exception of Italy and Denmark where per capita prescriptions are quite minimal, that is, <25 prescriptions per 1000 inhabitants (Molstad et ah, 2000). They are also widely used in animal husbandry where daily therapeutic doses of 40 mg tetracycline kg liveweight are typical (Kilhne et al., 2000). 

Following this line of work, we made the discoveries reported here. Before we indicate these, we note that the microarray datasets that we analyzed for tetracycline and chloroquine do not contain many differentially regulated reactions. The possibility remains that studying drug resistance mechanisms of the malaria parasites at the transcriptional level of their proteins is not reliable (Karine Le Roch, personal communication). 

In the so-called tetracycline case (2), there was evidence that in the preparation of aureomycin broth by the fermentation of S, aureo-faciens, some small percentage of tetracycline was coproduced. Aureomycin was known and produced by fermentation substantially before the discovery of tetracycline. The argument was raised by the patent examiner when the tetracycline application was in the Patent Office that tetracycline must be produced inherently in the fermentation in the production of aureomycin. The applicant was able to show, however, that the amount of tetracycline produced in the fermentation broth in aureomycin production was so small that it was of inconsequential value to mankind as an antibiotic. In fact, most methods of analysis did... 

Further antibiotics, mainly derived from actinomycetes, are used for special applications in human and veterinary medicine [20]. These compounds have numerous chemical structures. The macrolides, tetracyclines, aminoglycosides, glycopeptides, and ansamycins for instance are used in antibacterial treatment whereas the anthracyclines reached the market to supplement anticancer chemotherapy. The fairly toxic polyether-type antibiotics are preferably used as anticoccidial agents. Due to the dramatically increasing resistance of clinical important bacterial strains new targets for the discovery of novel types of antibacterial agents are urgently needed. 

After the Second World War, the effort continued to find other novel antibiotic structures. This led to the discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (Fig. 10.72) (1947), the tetracycline antibiotics (e.g. chlortetracycline (Fig. 10.71) (1948)), the macrolide antibiotics (e.g. erythromycin (Fig. 10.73) (1952)), the cyclic peptide antibiotics (e.g. cycloserine (1955)), and in 1955 the first example of a second major group of (3-lactam antibiotics, cephalosporin C (Fig. 10.41). 

It is fascinating to note the recent re-awakening of interest in bismuth therapies since the discovery in 1982 that the intestinal bacterium Helicobacter pylori may well initiate ulcer formation by excreting acid. Bismuth, in common with many heavy metals, is bactericidal and so the lasting effects of bismuth citrate therapy may well be a combination of ulcer healing (from the precipitates) as well as ulceration initiator suppression (from the bacteriocidal action). In vitro the organism is sensitive to bismuth but results in vivo are feeble. However, combinations of bismuth with antibiotics such as amoxicillin or tetracycline have success rates of 80%, i.e. four times the 20% success rate described above. 

In 1952, Conover developed tetracycline (Figure 1.20) from chlortetracycline by removal of its chlorine atom by catalytic hydrogenation, and then oxytetracycline. The discovery prompted an industry-wide search for superior structurally modified antibiotics, which has provided most of the important antibiotic discoveries made since then. 

Finland, M. Twenty-fifth anniversary of the discovery of Aureomycin the place of the tetracyclines in antimicrobial therapy. Clin. Pharmacol. Ther. 1974, 15, 3-8. 

A particularly rich contribution of this approach in the therapeutic area has been the discovery and the development of penicillin (see Chapter 1). It initiated the discovery of many other major antibiotics such as chloramphenicol, streptomycin, tetracyclines, rifampicine, etc. 

The successes achieved in the past decade with chemically modified penicillins, tetracyclines, and lincomycin, undoubtedly influenced the judgment of the panel that preparation of structural analogs of useful antibiotics by chemical or other means should be ranked as one of the two most promising discovery approaches for the next decade. Before proceeding further with the evaluation made by the respondents of the five approaches (Table VII), some aspects of the history and nature of the structural modification approach are examined. 

Robinson expressed this skepticism (45) when he wrote in 1953 .. . indeed one of the disappointments in antibiotic work is that it seems impossible to modify the molecule without reducing or eliminating its antimicrobial activity. . . The discoveries early in the 1950 s of tetracycline and phenoxymethylpenicillin established beyond doubt, however, that modification of antibiotics by chemical or biosynthetic means could yield superior drugs. 

Here as with the tetracyclines, the solution of difficult chemical problems was a prerequisite to successful new drug discovery. At first the counterpart of 6-aminopenicillanic acid could be made only in very low yields by chemical hydrolysis. A practical enzymatic hydrolysis of cephalosporin C to 7-aminocephalosporanic acid (7-ACA) was not found. R. B. Morin and co-workers provided the elegant solution (Figure 21) (101), which made the preparation of 7-ACA and semisynthetic cephalosporins possible on a practical scale. The impetus to persevere in this... 

The epoch-making discovery of chlortetracycline (aureomycin) in 1947 by Duggar paved the way for a number of structural analogues used as broad-spectrum antibiotics that belong to the tetracycline family. The tetracyclines which are found to be effective therapeutically are listed in the following table. 

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