Sensitivity to Analogs of Thiamine Pyrimidine Associated with Resistance To Amethopterin or Purine Antagonists.

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Abstract
Mutants of Bacillus subtilis resistant to amethopterin and of Escherichia coli resistant to 6-mercaptopurine, 8-aza-guanine and 6-thioguanine were employed with a simple agar-diffusion technic to test 245 compounds, including 175 pyrimidines, for cross-resistance or increased (collateral) sensitivity. Collateral sensitivity to amethopterin was found in 2 E. coli mutants. Collateral sensitivity to 3 chemical analogs of the pyrimidine moiety of thiamine was seen in both B. subtilis amethopterin-resistant mutants and an E. coli mutant resistant to the 3 purine antagonists. The 3 pyrimidines (all with 4-amino substituents), were 2-methylmercapto-5-hydroxy-methyl, 2-methylmercapto-5-ethoxymethyl and 2-ethylmercapto-5-chloromethyl compounds. Amethopterin-resistant B. subtilis mutants showed sensitivity to 2-mercapto-4-amino-5-hydroxymethyl and 2-ethylmercapto-4-amino-5-hydroxymethyl analogs, and cross resistance to 2-hydroxy-4-amino-5-aminomethyl pyrimidine. The inhibition produced by these thiamine pyrimidine analogs was specifically blocked by addition of thiamine pyrimidine, thiamine or thiamine pyrophosphate. These latter 3 metabolites also block growth inhibition by amethopterin.

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