International Journal of Antimicrobial Agents 2010-01-01

A new-generation 5-nitroimidazole can induce highly metronidazole-resistantGiardia lambliain vitro

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

文献索引：Int. J. Antimicrob. Agents 36(1) , 37-42, (2010)

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摘要

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 ID 90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID 90 values around 100 μM (MTR-susceptible isolates typically have an ID 90 of 5–12.8 μM). 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.