title: Reactivity of reduced [2Fe-2S] ferredoxins parallels host susceptibility to nitroimidazoles.
abstract: The kinetics of the electron transfer reaction between reduced [2Fe-2S] ferredoxins and select nitroimidazole antimicrobial agents is reported. The ferredoxins from the protozoan Trichomonas vaginalis and the cyanobacterium Anabaena sp. strain 7120 were studied because they are the proximal electron donors to nitroimidazoles in these two organisms with significantly different nitroimidazole susceptibilities. The rates of electron transfer from Anabaena ferredoxin to all nitroimidazoles were 1 to 2 orders of magnitude lower than for T. vaginalis ferredoxin. Quantitative structure-activity analysis of the kinetic data showed that the size of the alkyl substituent on the N-1 position of the imidazole ring strongly influenced the magnitude of the electron transfer rate constant. This implies that the distance between the iron-sulfur cluster and the nitro group of the imidazole is the critical variable in determining the rate of electron transfer. A correlation between the magnitude of the one-electron transfer rate constant with the susceptibility of the host organism to the cytotoxic effects of nitroimidazoles was also discovered. These results demonstrate that reductive activation is the most crucial step in determining the toxicity of nitroimidazoles.
authors.affiliation: Department of Chemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Momcilo
authors.initials: M
authors.lastname: Vidakovic
authors.forename: Chetlen R
authors.initials: CR
authors.lastname: Crossnoe
authors.forename: Christopher
authors.initials: C
authors.lastname: Neidre
authors.forename: Kyonghee
authors.initials: K
authors.lastname: Kim
authors.forename: Kurt L
authors.initials: KL
authors.lastname: Krause
authors.forename: Juris P
authors.initials: JP
authors.lastname: Germanas
mesh_terms: D000818:Animals; D005288:Ferredoxins / Q000187:drug effects* / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D005288:Ferredoxins; D009593:Nitroimidazoles