The specific resistance of tubercle bacilli to para-aminosalicylic acid and sulfonamides.

The observation by Youmans et al. (1947) that para-aminobenzoic acid (PABA) antagonizes the action of para-aminosalicylic acid (PAS) has been confirmed repeatedly. Since the role of PABA has come to assume such a central position in explaining the mechanism and site of action of the sulfonamides, the question now arises, Do PAS and the sulfonamides inhibit the same metabolic process? The development of resistant strains of microorganisms provides a means of investigating this problem. If we assume that the two drugs act at similar sites, then an independently developed strain resistant to sulfonamides should, a priori, be resistant to PAS and a PAS-resistant strain should likewise be resistant to the sulfonamides. Experiment 1. The development of a strain of Mycobacterium tuberculosis, H37Rv, highly resistant to PAS was accomplished by serial transfer through liquid sorbitan monooleate medium containing increasing concentrations of the drug. The resistant mutant grew well at a concentration of 500 uAg of PAS per ml of medium, whereas the parent strain H37Rv is inhibited by 0.1 Mgg of PAS per ml. These two strains were cultured in liquid sorbitan monooleate medium in the presence of different concentrations of sulfonamides and sulfonamidelike drugs. The results were recorded after 14 days of incubation (table 1). No differences were noted with regard to sensitivity to sulfonamides. Experiment 2. An independently developed strain of M. tuberculosis, H37Rv, highly resistant to sulfathiazole (ST) was obtained by serial transfers in sorbitan monooleate medium to which ST was added in increasing concentrations. The resistant strain showed good growth in 200 Mg of ST per ml, but the parent strain did not grow in 10 ,ug of drug per ml. These strains were cultured in concentrations of PAS ranging from 0.1 ,ug to 10 ,ug per ml of medium. The results were read after incubation for 14 days. Both strains were inhibited equally by PAS.