Elevated uridine nucleotide pools in fluorouracil/fluorouridine resistant mutants ofNocardia lactamdurans

Selection of spontaneous mutants ofNocardia lactamdurans MA2908 for resistance to 5-fluorouracil results in the simultaneous development of resistance to 5-fluorouridine. The resulting mutants fall into four distinct classes based on the amount of uracil accumulating in fermentation broths. An additional characteristic of these mutants is a reduction in the ability to incorporate exogenous uracil into nucleic acids even though transport and conversion to the nucleotide level appears normal. Finally, production of efrotomycin is increased in these mutants in both chemically defined and complex fermentation media to levels equivalent to those of MA4820, the first productivity mutant isolated in a conventional strain improvement program. Resistance development and uracil excretion are adequately explained by an elevation of the intracellular uridine nucleotide pool, in particular UMP. The role of the uridine necleotides in the efrotomycin fermentation is unknown.