A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

Dunn, Linda A.; Burgess, Anita G.; Krauer, Kenia G.; Eckmann, Lars; Vanelle, Patrice; Crozet, Maxime D.; Gillin, Frances D.; Upcroft, Peter; Upcroft, Jacqueline A.

doi:10.1016/j.ijantimicag.2010.03.004

« Previous Next »International Journal of Antimicrobial Agents
Volume 36, Issue 1 , Pages 37-42, July 2010

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

Linda A. Dunn
- Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia
Anita G. Burgess
- Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia
Kenia G. Krauer
- Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia
Lars Eckmann
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Patrice Vanelle
- Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et III – CNRS, UMR 6264: Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Maxime D. Crozet
- Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et III – CNRS, UMR 6264: Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Frances D. Gillin
- Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
Peter Upcroft
- Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia
Jacqueline A. Upcroft
- Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia
- Corresponding author. Present address: The Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Brisbane, Qld 4029, Australia. Tel.: +61 7 3362 0369; fax: +61 7 3362 0105.

Received 6 November 2009; accepted 3 March 2010. published online 26 April 2010.

Abstract

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID₉₀ values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID₉₀ values around 100μM (MTR-susceptible isolates typically have an ID₉₀ of 5–12.8μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells.