p-AMINOBENZOIC ACID 519 



strain, 385 it was suggested that the acquisition of sulfonamide-resistance 

 is a sudden, spontaneous "mutation" occurring continuously, but becom- 

 ing evident only when conditions are suitable for selective propagation 

 of resistant cells. 351 The gradual increase in resistance of Staphylococcus 

 aureus to sulfonamides occurring at random time during serial transfer 

 in sodium sulfathiazole 37C was interpreted to indicate mutation and 

 selection. The slow and apparently multiple process in obtaining resistant 

 strains of Bacterium lactis aerogenes and early stage reversal of resistance 

 in the absence of the inhibitor, indicating a slower growth rate for the 

 resistant strain, have been presented as evidence in favor of an adaptive 

 mechanism. 3S3 



From the standpoint of the permanence of resistance in organisms as 

 related to the clinical use of sulfonamides, it is of interest that the cultiva- 

 tion of a mixed population of sulfanilamide-resistant and susceptible 

 cells of Escherichia coli for 10 passages in synthetic media free of sulfa- 

 nilamide resulted in a "weeding out" of the resistant strain, as shown by 

 subsequent exposure of the culture to the drug. 344 



The converse of resistance is obtained by culturing in hemolyzed horse 

 blood staphylococci and some streptococci which are relatively insensitive 

 to sulfonamide. The organisms develop marked sensitivity to the sul- 

 fonamides. 386 



Mechanism of Resistance. A significant increase in production of 

 p-aminobenzoic acid or a related anti-sulfonamide compound over that in 

 parent or nonresistant strains has been observed in sulfonamicle-resistant 

 strains of Staphylococcus aureus, 18 - 353 - 371, 373 > 387, 389 gonococci, 334 strains 

 of Clostridium, 326 Brucella paramelitensis, 342 Escherichia coli, 340 strepto- 

 cocci, 340 Polytomella caeca, 104 Diplococcus pneumoniae, 340 ' 388, 390 and 



Table 9. The Inhibition Index and Minimum Inhibitory Concentration of 2-Sulfanil- 



amido-4-methylthiazole for Resistant and Original Strains of 



Staphylococcus aureus 127 



° Concentration necessary to reduce growth to one-third of controls. 



b Ratio of concentration of sulfamethylthiazole (0.001 M) to p-aminobenzoic acid. 



c Relative antisulfonamide activity against strain B of extracts prepared from the various strains. 



d Arbitrary value. 



