Trifluoromethionine, a prodrug designed against methionine gamma-lyase-containing pathogens, has efficacy in vitro and in vivo against Trichomonas vaginalis.
Methionine gamma-lyase, the enzyme which catalyzes the single-step conversion of methionine to alpha-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasite Trichomonas vaginalis, to anaerobic bacteria containing methionine gamma-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.
Coombs
G H
GH
Division of Infection & Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom. g.coombs@bio.gla.ac.uk
Mottram
J C
JC
D000818:Animals; D013437:Carbon-Sulfur Lyases / Q000494:pharmacology*; D002478:Cells, Cultured; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity
D011355:Prodrugs; C037646:trifluoromethionine; D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase