In vitro resistance to 5-nitroimidazoles and benzimidazoles in Giardia duodenalis: Variability and variation in gene expression

Argüello-García, Raúl; Cruz-Soto, Maricela; Romero-Montoya, Lydia; Ortega‐Pierres, Guadalupe

doi:10.1016/j.meegid.2009.05.015

Cited by 48 publications

(40 citation statements)

References 31 publications

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“…S3A in the supplemental material). It is important to note that others have previously found an overexpression of VSPs in drug-resistant clones of Giardia (43), which means that this feature is more frequent than it seems. Indeed, there is evidence that correlates the overexpression of VSPs with high virulence in Giardia isolates (44).…”

Section: Resultsmentioning

confidence: 91%

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Reyes‐Vivas

Mora

Castillo-Villanueva

et al. 2014

Antimicrob Agents Chemother

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Giardiasis is highly prevalent in the developing world, and treatment failures with the standard drugs are common. This work deals with the proposal of omeprazole as a novel antigiardial drug, focusing on a giardial glycolytic enzyme used to follow the cytotoxic effect at the molecular level. We used recombinant technology and enzyme inactivation to demonstrate the capacity of omeprazole to inactivate giardial triosephosphate isomerase, with no adverse effects on its human counterpart. To establish the specific target in the enzyme, we used single mutants of every cysteine residue in triosephosphate isomerase. The effect on cellular triosephosphate isomerase was evaluated by following the remnant enzyme activity on trophozoites treated with omeprazole. The interaction of omeprazole with giardial proteins was analyzed by fluorescence spectroscopy. The susceptibility to omeprazole of drug-susceptible and drug-resistant strains of Giardia lamblia was evaluated to demonstrate its potential as a novel antigiardial drug. Our results demonstrate that omeprazole inhibits giardial triosephosphate isomerase in a species-specific manner through interaction with cysteine at position 222. Omeprazole enters the cytoplasmic compartment of the trophozoites and inhibits cellular triosephosphate isomerase activity in a dose-dependent manner. Such inhibition takes place concomitantly with the cytotoxic effect caused by omeprazole on trophozoites. G. lamblia triosephosphate isomerase (GlTIM) is a cytoplasmic protein which can help analyses of how omeprazole works against the proteins of this parasite and in the effort to understand its mechanism of cytotoxicity. Our results demonstrate the mechanism of giardial triosephosphate isomerase inhibition by omeprazole and show that this drug is effective in vitro against drug-resistant and drug-susceptible strains of G. lamblia.

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Section: Resultsmentioning

confidence: 91%

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Reyes‐Vivas

Mora

Castillo-Villanueva

et al. 2014

Antimicrob Agents Chemother

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“…The mechanisms of Mz resistance appear to be diverse. In some but not all Mz-resistant (Mz r ) Giardia cell lines, decreases in PFOR levels and activity of ferredoxin are involved (2,8,24,37). Downregulation of PFOR most probably affects the glycolytic metabolism in Mz r Giardia, but that has not been determined conclusively.…”

mentioning

confidence: 99%

Impaired Parasite Attachment as Fitness Cost of Metronidazole Resistance in Giardia lamblia

Tejman-Yarden

Millman

Lauwaet

et al. 2011

Antimicrob Agents Chemother

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Infections with the diarrheagenic protozoan pathogen Giardia lamblia are most commonly treated with metronidazole (Mz). Treatment failures with Mz occur in 10 to 20% of cases and Mz resistance develops in the laboratory, yet clinically, Mz-resistant (Mz r ) G. lamblia has rarely been isolated from patients. To understand why clinical Mz r isolates are rare, we questioned whether Mz resistance entails fitness costs to the parasite. Our studies employed several newly generated and established isogenic Mz r cell lines with stable, high-level resistance to Mz and significant cross-resistance to tinidazole, nitazoxanide, and furazolidone. Oral infection of suckling mice revealed that three of five Mz r cell lines could not establish infection, while two Mz r cell lines infected pups, albeit with reduced efficiencies. Failure to colonize resulted from a diminished capacity of the parasite to attach to the intestinal mucosa in vivo and to epithelial cells and plastic surfaces in vitro. The attachment defect was related to impaired glucose metabolism, since the noninfectious Mz r lines consumed less glucose, and glucose promoted ATP-independent parasite attachment in the parental lines. Thus, resistance of Giardia to Mz is accompanied by a glucose metabolism-related attachment defect that can interfere with colonization of the host. Because glucose-metabolizing pathways are important for activation of the prodrug Mz, it follows that a fitness trade-off exists between diminished Mz activation and reduced infectivity, which may explain the observed paucity of clinical Mz r isolates of Giardia. However, the data also caution that some forms of Mz resistance do not markedly interfere with in vivo infectivity.

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“…Not yet defined, but in resistant strain rearrangements of chromosomes and cytoskeleton, and alteration of gene expression (VSPs, β-giardin) has been Morgan et al, 1993;MacDonald et al, 2004;Argüello-García et al, 2009 reported.…”

Section: -Nitroimidazole Compoundsmentioning

confidence: 99%

Combination therapy in the management of giardiasis: What laboratory and clinical studies tell us, so far

et al. 2016

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Treatment failures in patients suffering from giardiasis is not uncommon feature. The most frequent approach in these cases is to treat these patients with longer repeated courses and/or higher doses of the primary therapy, or using drugs from a different class to avoid potential cross-resistance. However, a higher rate of adverse events may limit this strategy. In this context, combination therapy (CT) is emerging as a valuable option against refractory giardiasis. In the attempt to evaluate the benefits of CT, a number of experimental studies, clinical series, and randomized clinical trials (RCTs), as well as several veterinary studies have been performed, with varying results. Here, we present a critical analysis of the available information regarding CT for the treatment of Giardia infection, as well as the authors' opinion with respect to its use. RCTs of combination therapy are limited and the optimal combinations and administration strategies need yet to be clarified. Analyses of the cost-effectiveness and RCTs of CTs for Giardia infection are required to assess the role of these drugs for the control of giardiasis, mainly in the case of treatment failures linked to suspected drug tolerance are the case. KeywordsGiardia To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. HighlightsTreatment failures are not uncommon in giardiasis.Published studies have shown combination therapy in giardiasis to be safe and effective.Observations encourage the study of combinations of metronidazole with albendazole or quinacrine.Combination therapy could be a useful alternative in the case of treatment failures linked to suspected drug tolerance. Treatment failures in patients suffering from giardiasis are not uncommon feature. The most frequent approach in these cases is to treat these patients with longer repeated courses and/or higher doses of the primary therapy, or using drugs from a different class to avoid potential cross-resistance. However, a higher rate of adverse events may limit this strategy. In this context, combination therapy (CT) is emerging as a valuable option against refractory giardiasis. In the attempt to evaluate the benefits of CT, a number of experimental studies, clinical series, and randomized clinical trials (RCTs), as well as several veterinary studies have been performed, with varying results. Here, we present a critical analysis of the available information regarding CT for the treatment of Giardia infection, as well as the authors' opinion with respect to its use. RCTs of combination therapy are limited and the optimal combinations and administration strategies need yet to be clarified. Analyses of the cost-effectiveness and RCTs of CTs for Giardia infection are required to assess the role of these drugs for the control of giardiasis, mainly in the case of treatment failures linked to suspected drug tolerance are the case.

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In vitro resistance to 5-nitroimidazoles and benzimidazoles in Giardia duodenalis: Variability and variation in gene expression

Cited by 48 publications

References 31 publications

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Impaired Parasite Attachment as Fitness Cost of Metronidazole Resistance in Giardia lamblia

Combination therapy in the management of giardiasis: What laboratory and clinical studies tell us, so far

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