In vitro-induction of metronidazole-resistant Giardia duodenalis is not associated with nucleotide alterations in the genes involved in pro-drug activation

Abstract

Giardiasis is an infectious disease caused by Giardia duodenalis. The pro-drug metronidazole (MTZ) is the first-line treatment for giardiasis. Parasite's proteins as pyruvate:ferredoxin oxidoreductase (PFOR), ferredoxin (Fd), nitroreductase-1 (NR-1) and thioredoxin reductase (TrxR) participate in MTZ activation. Here, we showed Giardia trophozoites long-term exposed to MTZ presented higher IC 50 than controls, showing the drug influenced the parasite survival. That reduction in MTZ's susceptibility does not seem to be related to mutations in the genes pfor, fd, nr-1 or trxr. It points that different mechanism as alterations in other metabolic pathways can account for Giardia resistance to MTZ therapy.

Antimicrobial resistance of the enteric protozoon Giardia duodenalis – A narrative review

“…Several conclusions can be drawn from the available data on antimicrobial resistance in G. duodenalis . The recorded multiple realizability of resistance, which can be mediated by various factors influencing the expression of multiple effector proteins without specific target gene mutations [ 62 ], is most likely due to epigenetic or posttranslational modifications [ 44 , 46 , 48 , 52 , 70 ] and does not require unambiguously identifiable patterns in proteomic assays [ 55 ]. Based on these findings including the results of comparative proteomics [ 55 ], it is highly unlikely to assume that rapid and easy-to-perform molecular assays for the detection of antimicrobial resistance will be available in the near future.…”

“…Matching the abovementioned, metronidazole resistance induced by long-term growth of G. duodenalis with sublethal metronidazole doses can occur completely without mutations in metronidazole resistance-associated genes like pfor, fd, nr-1 or trxr [ 62 ]. Nevertheless, some associations have been described.…”

Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity

“…Giardia spp. possess numerous potential sources of their activation, such as PFOR, ferredoxin, thioredoxin reductase, and several nitroreductases ( [125,290,291], and references therein). However, their individual contributions to the action of particular drugs remain a matter of debate.…”

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part I: Drug resistance

“…On the other hand, an American study conducted recently reported that although T. vaginalis virus was detected in 40% of their study population, it had no influence in clinical manifestations, reinfections and MTZ resistance [192] . In addition, based on the results obtained from two recently conducted studies [193,194] , German reviewers [195] attributed MTZ resistance to over-expression of various effector molecules without specific target gene mutations, i.e., epigenetic or posttranslational modifications without a recognized pattern in proteomic assays. They hypothesized that these modifications had essential roles in the parasite DNA with more significant effects than mutational base exchange [195] .…”