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Antimicrobial Agents and Chemotherapy, January 2003, p. 302-308, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.302-308.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Reactivity of Reduced [2Fe-2S] Ferredoxins Parallels Host Susceptibility to Nitroimidazoles

Momcilo Vidakovic,¹ Chetlen R. Crossnoe,² Christopher Neidre,³ Kyonghee Kim,¹ Kurt L. Krause,^2,4 and Juris P. Germanas^3*

Department of Chemistry,¹ Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204,² Department of Chemistry, Southern Methodist University, Dallas, Texas 75275,³ Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030⁴

Received 1 July 2002/ Returned for modification 20 August 2002/ Accepted 1 October 2002

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.

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* Corresponding author. Mailing address: Department of Chemistry, Southern Methodist University, Dallas, TX 75275. Phone: (832) 293-2043. Fax: (713) 526-8677. E-mail: germanas{at}mail.smu.edu.

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Antimicrobial Agents and Chemotherapy, January 2003, p. 302-308, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.302-308.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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