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Physiological aspects of nitro drug resistance in Giardia lamblia

Joachim Müller1, Andrew Hemphill1, Norbert Müller1

  • 1Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.

International Journal for Parasitology. Drugs and Drug Resistance
|May 9, 2018
PubMed

Insights

Drug resistance in Giardia lamblia is a growing concern. This study identifies metabolic adaptations, including reduced enzyme activity and altered energy levels, in resistant strains, offering insights into nitro drug resistance mechanisms.

Area of Science:

  • Microbiology
  • Parasitology
  • Biochemistry

Background:

  • Metronidazole and nitazoxanide are primary treatments for giardiasis.
  • Increasing resistance to these nitro compounds necessitates new research models.
  • Stable resistant strains are crucial for studying resistance mechanisms.

Purpose of the Study:

  • To generate and characterize a stable Giardia lamblia clone resistant to metronidazole and nitazoxanide.
  • To conduct a physiological comparison between resistant (C4) and wild-type (WBC6) Giardia lamblia strains.
  • To investigate the biochemical and metabolic basis of nitro compound resistance.

Main Methods:

  • Generation of a stable resistant Giardia lamblia clone (C4).
  • Comparative analysis of trophozoite ultrastructure.
  • Measurement of whole cell activities (oxygen consumption, resazurin reduction).
  • Assay of key enzyme activities (e.g., ornithine carbamoyltransferase).
  • Quantification of metabolic parameters (NAD(P)+/NAD(P)H, ADP/ATP ratios, FAD content).

Main Results:

  • Resistant C4 strain showed lower nitroreductase, oxygen consumption, and resazurin reduction activities.
  • Ornithine carbamoyltransferase activity was reduced in the resistant strain.
  • Reduced FAD and NADP(H) pool sizes and higher ADP/ATP ratios were observed in C4 trophozoites.
  • Nitroreductase activities were significantly lower in resistant strains.

Conclusions:

  • Nitro compound resistance in Giardia lamblia is linked to significant metabolic adaptations.
  • These adaptations involve a reduction in the activity of FAD-dependent oxidoreductases.
  • The findings provide a model for studying nitro drug resistance in parasitic protozoa.
Keywords:
AdaptationAnaerobiosisDiplomonadsOxidoreduction

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