SUMMARY: Strains of and resistant to small molecule inhibitors of dihydrofolate reductase were isolated under various nutritional conditions. When thymine and/or purines were available in the media, several of the isolated strains had nutritional requirements for these metabolites, but resistant lines could still be isolated in their absence. Thus, the biochemical alteration accompanying resistance could be predetermined to a major extent by the design of the experiment.

The wild-type strain of did not incorporate exogenous thymine, and was insensitive to thymine antagonists, while the thymine-requiring strain was highly sensitive to 5-bromouracil, dithiothymine and 2-thiothymine. This suggested that resistance was accompanied by the appearance of a permeability or transport system for thymine.


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