Inhibition Steps in Sulfonamide Bacteriostasis of Escherichia Coli.

The effectiveness of p-aminobenzoic acid (PABA) in overcoming sulfanilamide (SA) growth inhibition of Escherichia coli was explained on the basis that PABA was an essential metabolite and that SA interfered with -its utilization by the cell (Woods, 1940). Reversal of sulfonamide action by structurally unrelated metabolites such as methionine, xanthine, serine, thymine and valine (Shive, 1950; Winkler and de Haan, 1948; Winkler et al., 1949) was assumed to be due to their being products of PABA associated enzyme system(s). The activity of these metabolites in replacing the need for PABA in the nutrition of induced mutants of E. coli (Lampen et at., 1946, 1949) lent support to this interpretation. Pteroylglutamic acid (PGA) is known to overcome sulfonamide inhibition non-competitively and to replace the PABA requirement of certain organisms (Lampen and Jones, 1946, 1947). PGA is, however, inactive with E. coli, though the organism is known to elaborate a factor with folic acid (FA) activity, this synthesis being inhibited by sulfonamides (Lascelles and Woods, 1952). Vitamin B12 has been reported (Shive, 1950) to potentiate PABA action as, in its presence, higher concentrations of SA are required to inhibit the biosynthesis of methionine, xanthine and serine. Also vitamin B12 is known to decrease the PABA requirement for a PABA auxotroph of E. coli (Davis, 1951; Gots and Chu, 1952). In combination with methionine, it further decreases the need for PABA (Gots and Chu, 1952). The foregoing and other known relationships among PABA, FA and vitamin B12 suggested a study of their effects in the reversal of sulfonamide action by the antagonists reported by Shive (1950) and Winkler and de Hann (1948). Such a study was also indicated by our observation that, with sulfadiazine (SD) as inhibitor and at rather high concentrations of the drug, the non-competitive antagonists reported by Winkler et al. (1950) in E. coli were no longer sufficient to reverse growth inhibition. A preliminary report has appeared (Alimchandani and Sreenivasan, 1955a).