In studies dealing with the mode of action of sulfonamides, one of the objectives is to obtain information regarding the action of drugs in the highly complex environment in vivo. It is likewise the objective of such studies to demonstrate why certain drugs are most effective against certain bacteria, and others are completely ineffective. To correlate the results of in vitro studies with those This investigation has been aided by a grant from The Josiah Macy, Jr., Foundation.
Studies previously reported on the mode of action of sulfonamides on bacteria showed that the inhibition of respiratory enzymes of the bacteria caused a proportional inhibition of the growth of Streptococcus pyogenes and pneumococcus, type I. This conclusion was based on simultaneous measurements, at various time intervals, of the increase in the number of bacteria (and the mg of bacterial nitrogen) and of the respiration in the presence and absence of 0.04 M sulfanilamide. On the basis of these and other observations, the "inhibition of respiration theory," as the mode of action of sulfonamides, was proposed (Sevag and Shelburne, 1942a, 1942b). This theory, in part, stated that chemotherapeutic agents which possess structural similarity to the whole or part of the coenzyme molecules may specifically combine with the protein component of the respiratory enzymes. This combination may take place as a result of the displacement of coenzymes by the drug, forming an inactive "enzyme analogue," or by a reversible union of the drug with the protein, forming an inactive "drug-proteincoenzyme complex." In this connection it was shown (Sevag, Shelburne, and
In two previous reports, it was shown that cocarboxylase and p-aminobenzoic acid counteract the inhibitory effect of sulfathiazole on yeast and bacterial carboxylases. Whereas cocarboxylase brings about this effect without exercising any inhibitory action on carboxylase, p-aminobenzoic acid exercises the antagonistic action to sulfathiazole while maintaining a certain degree of inhibitory effect of its own on carboxylases. That is, p-aminobenzoic acid behaves as an inhibitor and thereby counteracts the effect of other inhibitors weaker or stronger than itself.In the preceding studies, the experimental conditions were such that cells, exercising carboxylase activity, could not multiply. In the present study, the antagonism between proteins and sulfonamides was investigated. Under these conditions cells multipled; and growth was estimated from measurements of turbidity with the Klett-Summerson photoelectric colorimeter. To correlate the weight of cells with their carboxylase activity at a given time, the bacterial turbidity was measured immediately after the last manometric reading. To obtain approximate values, the averages of initial and final numerical values were calculated. They are given in the following tables. These, no doubt, do not represent absolute values. However, since, in a study of this nature, only the comparative values are of significance, the expressed average results do not involve errors of a serious nature. RESULTSReversal by neopeptone of the inhibition of carboxylase activity of Staphylococcus aureus and Escherichia coli by sulfathiazole The results presented in table 1 with Staphylococcus aureus show that in a buffer mixture the carboxylase activity of staphylococci is inhibited 63 per cent by 4.14 X 10-3 M sulfathiazole. This inhibition is reduced to 35 and 20 per cent, respectively, by 0.043 and 0.172 per cent neopeptone. This corresponds to from 44 to 68 per cent reversal of inhibition.The results of experiments with Escherichia coli are presented in table 2.
In a preceding report it was shown that cocarboxylase antagonizes the inhibitory effect exercised by sulfathiazole on the carboxylase activities of (a) whole yeast cells, (b) yeast cells washed with alkaline phosphate, and (c) Staphylococcus aureus. The results showed that one molecule of cocarboxylase counteracted the inhibitory effect of 322 to 53,400 molecules of sulfathiazole on yeast carboxylase, and the inhibitory effect of 215 molecules of sulfathiazole on Staphylococcus aureus. The present report deals with experiments in which the antagonism between sulfathiazole and p-aminobenzoic acid is determined. RESULTS 1 This investigation has been aided by a grant from the Josiah Macy, Jr., Foundation.
The Global Alliance for the Future of Food provides a case exemplar of incorporating systems thinking, complexity understandings, and developmental evaluation into systems transformation work. This transformational engagement is not just rhetoric but is deeply embedded as the focus of the Global Alliance's ongoing work. It is, importantly, predicated on in‐depth and long‐term cocreation and collaboration between alliance leadership and an independent external evaluator. This chapter will tell the story of how the Global Alliance incorporated systems thinking, complexity understandings, and principles‐focused developmental evaluation into systems transformation work through the reflective practice of the coauthors, Ruth Richardson, the Global Alliance Executive Director, and Michael Quinn Patton, the developmental evaluation consultant to the Global Alliance.
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