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Antimicrobial Agents and Chemotherapy, March 2007, p. 868-876, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01159-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiparasitic Drug Nitazoxanide Inhibits the Pyruvate Oxidoreductases of Helicobacter pylori, Selected Anaerobic Bacteria and Parasites, and Campylobacter jejuni{triangledown}

Paul S. Hoffman,1,2,4,5* Gary Sisson,4 Matthew A. Croxen,1,2,4 Kevin Welch,3 W. Dean Harman,3 Nunilo Cremades,6,7 and Michael G. Morash4

Department of Medicine, Division of Infectious Diseases and International Health,1 Department of Microbiology,2 Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908,3 Department of Microbiology and Immunology,4 Department of Medicine, Division of Infectious Diseases, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7,5 Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza,6 Biocomputing and Physics of Complex Systems Institute, Zaragoza, Spain7

Received 15 September 2006/ Returned for modification 7 November 2006/ Accepted 1 December 2006

Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (Ki, 2 to 10 µM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO2) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and 1H nuclear magnetic resonance analyses determined that the spectral shift (A418 to A351) of NTZ was due to protonation of the anion (NTZ–) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pKa = 6.18). We propose that NTZ– intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.

* Corresponding author. Mailing address: Division of Infectious Diseases and International Health, Room 2146, MR-4 Bldg., 409 Lane Road, University of Virginia Health Systems, Charlottesville, VA 22908-1340. Phone: (434) 924-2893. Fax: (434) 924-0075. E-mail: psh2n{at}virginia.edu.

{triangledown} Published ahead of print on 11 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 868-876, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01159-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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