title: A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro.
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 Giardialamblia 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 microM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID(90) values around 100 microM (MTR-susceptible isolates typically have an ID(90) of 5-12.8 microM). 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.
authors.affiliation: Molecular Genetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4006, Australia.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Dunn
authors.forename: Anita G
authors.initials: AG
authors.lastname: Burgess
authors.forename: Kenia G
authors.initials: KG
authors.lastname: Krauer
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
authors.forename: Maxime D
authors.initials: MD
authors.lastname: Crozet
authors.forename: Frances D
authors.initials: FD
authors.lastname: Gillin
authors.forename: Peter
authors.initials: P
authors.lastname: Upcroft
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Upcroft
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D005609:Free Radicals / Q000037:antagonists & inhibitors; D016829:Giardia lamblia / Q000187:drug effects*; D008795:Metronidazole / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000378:metabolism; D050743:Pyruvate Synthase / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D005609:Free Radicals; D009593:Nitroimidazoles; D015800:Protozoan Proteins; D008795:Metronidazole; D050743:Pyruvate Synthase; C052587:4-nitroimidazole
references.citation: Expert Opin Drug Saf. 2003 Nov;2(6):529-41
references.pmid: 14585063
references.citation: PLoS Biol. 2007 Aug;5(8):e211
references.pmid: 17676992
references.citation: J Antimicrob Chemother. 1993 Jan;31(1):9-20
references.pmid: 8444678
references.citation: Clin Microbiol Rev. 2001 Jan;14(1):150-64
references.pmid: 11148007
references.citation: Mol Biochem Parasitol. 2000 Apr 30;108(1):137-40
references.pmid: 10802327
references.citation: Clin Microbiol Rev. 2008 Oct;21(4):639-65
references.pmid: 18854485
references.citation: Antimicrob Agents Chemother. 2006 Jan;50(1):344-7
references.pmid: 16377707
references.citation: J Antimicrob Chemother. 1985 Nov;16(5):589-95
references.pmid: 4077772
references.citation: Infect Genet Evol. 2009 Dec;9(6):1057-64
references.pmid: 19481175
references.citation: Microbiology (Reading). 2002 Aug;148(Pt 8):2467-2477
references.pmid: 12177340
references.citation: Trans R Soc Trop Med Hyg. 1992 Sep-Oct;86(5):521-2
references.pmid: 1475822
references.citation: Antimicrob Agents Chemother. 2009 Feb;53(2):458-64
references.pmid: 19015349
references.citation: J Antimicrob Chemother. 2000 Nov;46(5):819-21
references.pmid: 11062206
references.citation: J Antimicrob Chemother. 1984 Nov;14(5):449-61
references.pmid: 6511706
references.citation: J Med Chem. 2009 Jul 9;52(13):4038-53
references.pmid: 19480409
references.citation: Trans R Soc Trop Med Hyg. 1988;82(1):104-6
references.pmid: 3176140
references.citation: Microb Drug Resist. 1996 Fall;2(3):303-8
references.pmid: 9158790
references.citation: J Antimicrob Chemother. 2004 Oct;54(4):711-21
references.pmid: 15347633
references.citation: Eur J Biochem. 1996 Oct 1;241(1):155-61
references.pmid: 8898901
references.citation: J Antimicrob Chemother. 2007 Aug;60(2):280-7
references.pmid: 17561498
references.citation: Mol Microbiol. 2000 Apr;36(2):447-56
references.pmid: 10792730
references.citation: Eur J Biochem. 1994 Mar 1;220(2):439-46
references.pmid: 8125101
references.citation: Antimicrob Agents Chemother. 2001 Jun;45(6):1810-4
references.pmid: 11353630
references.citation: Cell Res. 2003 Aug;13(4):239-49
references.pmid: 12974614
references.citation: Clin Microbiol Rev. 2002 Jul;15(3):329-41
references.pmid: 12097242
references.citation: Surgery. 1983 Jan;93(1 Pt 2):165-71
references.pmid: 6849201
references.citation: Mol Microbiol. 2009 Apr;72(2):518-36
references.pmid: 19415801
references.citation: Eur J Med Chem. 2009 Feb;44(2):653-9
references.pmid: 18590939
references.citation: Drug Resist Updat. 1998;1(3):166-8
references.pmid: 17092801
references.citation: Drug Resist Updat. 1999 Oct;2(5):289-294
references.pmid: 11504503
references.citation: Parasitology. 1996 Mar;112 ( Pt 3):309-13
references.pmid: 8728994
references.citation: Acta Trop. 1995 Sep;60(1):35-46
references.pmid: 8546037
references.citation: Mol Biochem Parasitol. 1996 Aug;79(2):183-93
references.pmid: 8855555
references.citation: Antimicrob Agents Chemother. 1999 Jan;43(1):73-6
references.pmid: 9869568