Drug resistance in Giardia duodenalis.
Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protist's unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen.
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Cnr Park Dr and Flemington Rd, Parkville, VIC 3010, Australia. Electronic address: bransell@unimelb.edu.au.
Brendan R E
BR
Ansell
Bio21 Institute, University of Melbourne, 30 Flemington Rd, Parkville, VIC 3010, Australia.
Malcolm J
MJ
McConville
Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden.
Showgy Y
SY
Ma'ayeh
Bio21 Institute, University of Melbourne, 30 Flemington Rd, Parkville, VIC 3010, Australia.
Michael J
MJ
Dagley
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Cnr Park Dr and Flemington Rd, Parkville, VIC 3010, Australia.
Robin B
RB
Gasser
Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden.
Staffan G
SG
Svärd
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Cnr Park Dr and Flemington Rd, Parkville, VIC 3010, Australia.
Aaron R
AR
Jex
D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use; D001393:Azoles / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D016829:Giardia lamblia; D005873:Giardiasis / Q000188:drug therapy / Q000469:parasitology; D006801:Humans; D017211:Treatment Failure
D000981:Antiprotozoal Agents; D001393:Azoles
Drug resistance; Furazolidone; Giardia; Metronidazole; NAD(P)H oxidoreductase; Nitazoxanide; Nitroheterocyclic; Sir2 NAD-dependent histone deacetylase; Treatment failure