Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics

  title={Benznidazole Biotransformation and Multiple Targets in Trypanosoma cruzi Revealed by Metabolomics},
  author={Andrea Trochine and Darren John Creek and Paula Faral-Tello and Michael P. Barrett and Carlos Robello},
  journal={PLoS Neglected Tropical Diseases},
Background The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn. Methodology/Principal findings Parasites treated with… 

Figures from this paper

A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism

It is proposed that TcAKR contributes to benznidazole resistance by the removal of toxic glyoxal, and three of the four enzymes studied here display activity as prostaglandin F2α synthases, despite the fact that there are no credible cyclooxygenases in these parasites to account for formation of the precursor PGH2 from arachidonic acid.

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Although TcAKR uses Bz as the substrate, TcakR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases.

The thiol-polyamine metabolism of Trypanosoma cruzi: molecular targets and drug repurposing strategies.

The state of the art of the thiol-polyamine metabolism of T. cruzi is critically reviewed and drug repurposing emerged as a valid strategy to identify new biological activities for drugs in clinical use, while significantly shortening the long time and high cost associated with de novo drug discovery approaches.

Trypanosoma cruzi Mitochondrial Peroxiredoxin Promotes Infectivity in Macrophages and Attenuates Nifurtimox Toxicity

The results suggest a protective role of MPX holdase activity toward NFX toxicity, and confirm the importance of peroxidase activity during macrophage infection and provide insights for the relevance ofMPX hold enzyme activity in NFX resistance.

Anti-parasitic effect of vitamin C alone and in combination with benznidazole against Trypanosoma cruzi

The combination of vitamin C with benznidazole could be considered as an alternative treatment for Chagas’ disease and a 100% survival was observed and the weight loss occurring during the acute phase of the infection was reduced.

Unravelling metabolism of Leishmania by metabolomics

It remains unclear why deletion of TKT is lethal for amastigotes, increased sensitivity to oxidative stress or drop in mannogen levels may contribute, but no definite conclusions can be made.

Metabolomics, lipidomics and proteomics profiling of myoblasts infected with Trypanosoma cruzi after treatment with different drugs against Chagas disease

The metabolic fingerprinting approach to a complex host-cell parasite system is validated and could potentially be applied in the early stage of drug discovery and could help to prioritize early leads or reconfirmed hits for further development.



Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

These experiments indicate that the reduction of benznidazole by type I nitroreductase activity leads to the formation of highly reactive metabolites and that the expression of this enzyme is key to the trypanocidal properties displayed by the prodrug.

Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites*

The experiments indicate that the basis for the selectivity of nifurtimox against T. brucei lies in the expression of a parasite-encoded type I nitroreductase, which is shown to inhibit both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug.

Trypanocidal activity of nitroaromatic prodrugs: current treatments and future perspectives.

Recognition that this enzyme is responsible for activation of nitroheterocyclic prodrugs has allowed screening for compounds that preferentially target the parasite, and led to the identification of two new classes of anti-trypanosomal agents, nitrobenzylphosphoramide mustards and aziridinyl nitro Benzamides.

A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes

It is reported that in trypanosomes, both drugs are activated by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), and that down-regulation of this explains how resistance may emerge.

A Key Role for Old Yellow Enzyme in the Metabolism of Drugs by Trypanosoma cruzi

Interestingly, immunoprecipitation experiments revealed that anti-TcoyE polyclonal antibody abolished major reductase activities of the lysates toward these drugs, identifying TcOYE as a key drug-metabolizing enzyme by which quinone drugs have their mechanism of action.

Unveiling Benznidazole's mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi

It is suggested that BZ preferentially oxidizes the nucleotide pool, and the extensive incorporation of oxidized nucleotides during DNA replication leads to potentially lethal double‐stranded DNA breaks in T. cruzi DNA.

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

It is discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronIDazole activation in E. histolytica with a central role for thiOREDoxin reduCTase.

Sterol 14-demethylase inhibitors for Trypanosoma cruzi infections.

  • F. Buckner
  • Biology, Medicine
    Advances in experimental medicine and biology
  • 2008
Data has been published demonstrating synergistic activity of azole drugs with various other compounds, indicating that combination chemotherapy may be an effective strategy as this field moves ahead, and additional effort to develop better drugs needs to be a priority.

Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei

Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine.