The Mechanism of Resistance to Sulfonamides

Abstract

The Woods-Fildes theory and its extension by Landy et al. is based on the assumption that the resistance of bacteria to sulfonamides is due to the formation of para-aminobenzoic acid (PABA). To test this hypothesis, the arylamine formed by S. aureus (see paper I) was detd. and calculated as PABA. Using the resistant strain, growth in the presence of glucose was not inhibited by 0.04 [image] sulfanilamide (SA). The molar ratio of SA to calculated "PABA" was 2985. However, in the presence of pyruvate, growth was inhibited 75% despite the fact that a greater amt. of arylamine was formed resulting in a 21% smaller SA/"PABA" ratio. In some susceptible strains more than enough arylamine (calculated as "PABA") was formed to counteract sulfonamide action. Nevertheless, growth was strongly inhibited. Using the resistant strains in the presence of glucose and 0.0066 [image] sulfathiazole, the amt. of arylamine was-10-20 times smaller than that required to overcome the effect of sulfathiazole (ST). Nevertheless, there was no inhibition of growth in the presence of 0.0066 [image] ST. These results show that there is no correlation between the amt. of arylamine formed and resistance to sulfonamides. If PABA is present in these arylamines, it apparently is not in sufficient conc. to influence the results. A more reasonable explanation of sulfonamide action, consistent with the known biochemical requirements of the cell, can be made from considerations of the glucose and tryptophane metabolism of S. aureus. The utilization of glucose and the inhibition of the synthesis or utilization of tryptophane appear to be possible mechanisms. Glucose apparently makes possible the synthesis of tryptophane (see paper III). The resistant strain which previously was susceptible to sulfonamides in amino acid medium (in the absence of glucose) became resistant under the above conditions upon repeated daily transplantation on extract agar. This shows the possibility of alternate metabolic pathways for the manifestations of resistance to sulfonamides.