Pyruvate:ferredoxin oxidoreductase and thioredoxin reductase are involved in 5-nitroimidazole activation while flavin metabolism is linked to 5-nitroimidazole resistance in Giardia lamblia

Leitsch, David; Burgess, Anita; Dunn, Linda A.; Krauer, Kenia G.; Tan, Kevin S. W.; Duchêne, Michael; Upcroft, Peter; Eckmann, Lars; Upcroft, Jacqueline

doi:10.1093/jac/dkr192

Cited by 104 publications

(156 citation statements)

References 51 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…Mz resistance is functionally heterogeneous, with several causative mechanisms for each of the target microbes and between different microbes (7,24). For example, resistance in Giardia involves down-regulation of nitro drug-activating systems, including different reductases and redox proteins and metabolites (11,25), whereas Trichomonas also produces resistance proteins that directly detoxify nitro drugs (12) and Bacteroides has transporters that can remove nitro drugs from the cell (26). Despite this mechanistic diversity, for each of the resistant microbes, we were able to identify nitro compounds that could combat resistance, and some compounds were broadly effective against different resistant microbes.…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise mechanistic reasons for this counterintuitive observation remain to be determined, 5-NIs can be activated by different microbial pathways and probably target multiple microbial molecules (11,12,23) whose relative importance may depend on the compound and microbe. Because the specific target molecules of 5-NI drugs are not fully understood (23), a strategy focused on achieving effective whole-cell antimicrobial activity in the relevant systems may be the best choice for making rapid progress in developing improved antimicrobials in the clinically indispensable 5-NI class.…”

Section: Discussionmentioning

confidence: 99%

“…In some cases, Mz resistance can be overcome by treatment with other 5-NI drugs, but many resistant microbial strains exhibit cross-resistance between the major currently available 5-NI drugs (9). Multiple mechanisms have been implicated in 5-NI drug resistance, including a diminished capacity to reduce and activate 5-nitro prodrugs (10,11) and detoxification of nitro drug radicals (12).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.infectious diseases | antibiotics | medicinal chemistry

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Recombinant Giardia thioredoxin reductase (GlTrxR) (XP_001707168) was amplified from DNA of G. lamblia 106, purified, cloned, and expressed in arabinose-inducible Escherichia coli BL21-AI as described previously (16). TrxR activity was assayed in 100 mM potassium phosphate buffer (pH 6.25) containing 150 nM GlTrxR and 200 M NADPH by following the reduction of 1 mM 5,5=-dithiobis(2-nitrobenzoate) (DTNB) at ϭ 412 nm (⌬ε ϭ 13.6 mM Ϫ1 cm Ϫ1 ) (16).…”

Section: Methodsmentioning

confidence: 99%

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

Tejman-Yarden

Miyamoto

Leitsch

et al. 2013

Antimicrob Agents Chemother

133

117

View full text Add to dashboard Cite

Giardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity against Giardia lamblia. We identified 56 compounds that caused significant inhibition of G. lamblia growth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergent G. lamblia isolates representing both humanpathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficacious in vivo, as it eradicated infection with different G. lamblia isolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains. Giardiasis is one of the most common human parasitic infections of the intestinal tract worldwide, affecting hundreds of millions of people, mostly in developing countries. It has been included in the Neglected Diseases Initiative of the WHO (1). Giardia exists in two forms, the infectious cyst and the diseasecausing trophozoite that colonizes the small intestinal lumen. Cysts are spread through drinking water, food, and person-toperson contact. The clinical symptoms of giardiasis include diarrhea, abdominal pain, malabsorption, and weight loss. A recent cohort study following a major giardiasis outbreak in Norway showed that infection with Giardia lamblia was associated with a high prevalence of irritable bowel syndrome and chronic fatigue 3 years after acute illness (2), highlighting the major health impact of giardiasis even in areas where it is not endemic. Treatment of giardiasis relies on antimicrobial drug therapy, most commonly with 5-nitroheterocyclic drugs, particularly metronidazole and, more recently, nitazoxanide (3). However, cross-resistance among 5-nitro antimicrobials exists, and treatment failures occur in up to 20% of cases (4-6). Alternative antimicrobials exist, but these are generally less effective than 5-nitro drugs (3, 7).One important strategy in the development of new antimicrobials is the screening of e...

show abstract

“…Lalle, 2010;Upcroft and Upcroft, 2001;Leitsch et al, 2011;Leitsch et al, 2012;Muller et al, 2013;Uzlikova and Nohynkova,2014 …”

Section: -Nitroimidazole Compoundsmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Pyruvate:ferredoxin oxidoreductase and thioredoxin reductase are involved in 5-nitroimidazole activation while flavin metabolism is linked to 5-nitroimidazole resistance in Giardia lamblia

Abstract: These data add to the mounting evidence against the dogma that PFOR/Fd is the only couple with a low enough redox potential to reduce metronidazole in anaerobes and point to the multi-factorial nature of metronidazole resistance.

Cited by 104 publications

References 51 publications

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

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

Contact Info

Product

Resources

About