Restriction of bacterial growth by inhibition of polyamine biosynthesis by using monofluoromethylornithine, difluoromethylarginine and dicyclohexylammonium sulphate.
Bacterial growth was measurably slowed by a combination of drugs which inhibit polyamine-biosynthetic enzymes. Addition of DL-alpha-monofluoromethylornithine, which was shown to inactivate irreversibly ornithine decarboxylase extracted from Escherichia coli (Ki = 0.36 mM) and Pseudomonas aeruginosa (Ki = 0.30 mM), DL-alpha-difluoromethylarginine and dicyclohexylammonium sulphate to cultures of E. coli or P. aeruginosa resulted in a 40 and 70% increase in generation times (decreased growth rates) respectively, which was completely reversed by the addition of 0.1 mM-putrescine plus 0.1 mM-spermidine to the medium. Decreased intracellular polyamine concentrations correlated with increased generation times; putrescine concentration was decreased by 70% in E. coli and 80% in P. aeruginosa, while spermidine concentration was decreased by 50% in E. coli and 95% in P. aeruginosa. Subsequent investigation of the inactivation of the ornithine decarboxylase by monofluoromethylornithine indicated that it was active-site directed, as the normal substrate ornithine slowed the rate of inhibition. Specific interference with polyamine biosynthesis may be a viable approach to control of some bacterial infections.
D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003514:Cyclohexylamines; D003864:Depression, Chemical; D000518:Eflornithine / Q000031:analogs & derivatives*; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000096:biosynthesis*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*
D003514:Cyclohexylamines; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D000644:Quaternary Ammonium Compounds; C011769:dicyclohexylamine; C030965:alpha-(difluoromethyl)arginine; C037000:2-fluoromethylornithine; D001120:Arginine; D009952:Ornithine; D000518:Eflornithine