Mechanism of action of purpuromycin.
Purpuromycin, an antibiotic active against both fungi and bacteria, shows different modes of action against these two kinds of micro-organisms; in Candida albicans it inhibits RNA synthesis, whereas in Bacillus subtilis protein synthesis is primarily affected, with DNA and RNA synthesis blocked at higher concentrations of the drug. In bacterial cell-free protein-synthesis systems, purpuromycin did not inhibit synthesis from endogenous mRNA (elongation of peptides initiated within the intact cell) but inhibited MS2-phase RNA-dependent protein synthesis (which requires initiation) by 50% at 0.1 mg/l. Poly(U)-directed polyphenylalanine synthesis was 50% inhibited by 20 mg of purpuromycin/l when added to a complete system; however, when purpuromycin was preincubated with ribosomes dissociated into 30 S and 50 S subunits, the concentration for 50% inhibition fell to 0.1 mg/l. By contrast, in a C. albicans cell-free system poly(U)-directed polyphenylalanine synthesis was partially inhibited only at 200 mg/l. Purpuromycin also inhibited polynucleotide synthesis in vitro in reactions using Escherichia coli or wheat-germ RNA polymerases or E. coli DNA polymerase I. We suggest that in bacteria the primary target of purpuromycin is on ribosomes and that its action precedes the elongation step of protein synthesis. The effect on nucleic acid synthesis in both fungi and bacteria may be due to interaction of purpuromycin with DNA.
Landini
P
P
Marion Merrel Dow Research Institute, Lepetit Research Center, Varese, Italy.
Corti
E
E
Goldstein
B P
BP
Denaro
M
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004269:DNA, Bacterial / Q000096:biosynthesis; D004271:DNA, Fungal / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D046911:Macromolecular Substances; D009285:Naphthoquinones / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004269:DNA, Bacterial; D004271:DNA, Fungal; D046911:Macromolecular Substances; D009285:Naphthoquinones; C009115:purpuromycin; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase