Synthesis and the lethality of bleomycin in bacteria.

The bleomycins are antitumor agents composed of various cationic amides of a common inactive bleomycinic acid. At 1 mug/ml at 37 degrees, the naturally occurring spermidine derivative of bleomycin (A5) was far more lethal to Escherichia coli than were several other bleomycins tested. An exponential loss of viability was produced for 2 hr in various strains of E. coli growing in a synthetic medium. In the stringent E. coli, strain 15 TAU (thymine-arginine-uracil) rel A+ (arginine), withholding thymine did not affect the rate of killing. However, uracil starvation completely blocked killing by the antibiotic. Arginine deprival partially inhibited bleomycin killing in the stringent cell but had little effect on the lethality of the antibiotic in a relaxed isogenic strain actively synthesizing RNA. Similar results were obtained with another isogenic pair, stringent CP78 and relaxed CP79. Thus, the lethality of the antitumor agent, bleomycin, which is reported to produce breaks in bacterial and animal cell DNA in vivo and in vitro appeared totally dependent on RNA synthesis in E. coli. Nevertheless, chloramphenicol, which blocks protein synthesis and relaxes RNA synthesis in the stringent strains, also significantly inhibited the lethal action of the antibiotic, reducing the exponential rate of killing.