Doctor of Philosophy
Alfred N. Martin
Tetracyclines, originally isolated in the late 1940's and early 1950's from the mycelium of Streptomyces, have achieved major importance as therapeutic and prophylactic agents against a wide range of infections in human and veterinary medicine. They have also achieved great importance in agriculture where they are widely used to promote weight gain in livestock. Commercial production, during 1958 in the United States alone was 120 tons with a value of approximately $1 million per ton.
The clinical importance of these compounds has stimulated efforts to define their mode of action as inhibitors of bacterial reproduction. Antibiotics having as many functional groups as the tetracyclines may have many modes of action. The problem facing the research worker is to determine the relative contribution of each mode of action in a given biological system as a function of antibiotic concentration. If all parts of a biological system are exposed to an equivalent antibiotic concentration, one might expect that the degree of inhibition of the various sub-component systems would be proportional to the relative stabilities of the reaction products of the antibiotic and the sub-component system. The most critical reaction from the standpoint of cellular reproduction would then represent the point of the primary biochemical lesion or the site of action. The type of reaction would be the mode of action for the biological system. For a given biological system it is probable that there is one critical reaction which is most sensitive to the antibiotic, but this reaction may not be the same for every biological system (see Snell and Cheng (l) for an excellent discussion of the difficulties of defining a mode of tetracycline action). Many investigators presently feel that the primary biochemical lesion inflicted upon susceptible bacteria by tetracyclines is a general inhibition of protein synthesis (2,3,4). Therefore it was felt that the study of several measures of inhibition, particularly cell reproduction and protein synthesis, in the presence of several tetracyclines might be a useful way of studying modes of tetracycline action.
Biological activities of a large number of compounds obtained quantitatively under identical conditions and in a precise manner are required to establish structure-activity relationships. Presently available activities for tetracycline antibiotics have been summarized by Barrett (5), Boothe (6) and Plakunov (7). Many of these activities have been obtained under conditions such that the results parallel clinical activities. Thus, some compounds may not have achieved equilibrium with the test system. Some activities have been obtained for the purpose of studying antibiotic resistance while still others have been obtained in widely varying and not easily interrelatable biological test systems. Consequently, quantitative activities suitable for structure-activity relationships have not been reported for most tetracyclines.
The present work was undertaken to obtain activities suitable for structure-activity relationships and which are pertinent to both bacterial reproduction and the proposed mode of action. The activities obtained should include both clinically active and “inactive” tetracycline antibiotics.
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