New drug discovery strategies for the treatment of benznidazole-resistance in Trypanosoma cruzi, the causative agent of Chagas disease

ABSTRACT

Introduction

Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD.

Areas covered

Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi, aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD.

Expert opinion

Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.

KEYWORDS:

• Chagas disease
• benznidazole
• drug resistance
• novel treatments
• drug formulations
• drug combinations

Article highlights

• Chagas disease (CD), a neglected tropical disease, is caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). It is endemic in several Latin American countries as well as an emerging health problem in other countries including the United States, Australia, Japan and Spain.

• Benznidazole (BZ), the drug of choice for treating Chagas disease (CD), has significant limitations, including parasite resistance.

• Resistance to BZ is a complex process related to several metabolic pathways, whose mechanism is still under investigation.

• Susceptibility to BZ varies depending on the parasite life stage and among different T. cruzi DTUs and strains.

• New drug formulations and drug combinations provide strategies to overcome BZ resistance and find effective treatments for CD.

Declaration of interest

TJWJD Lapierre was awarded a scholarship from FAPEMIG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported through funding from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grants 408208/2018-0 (awarded to CO Rezende Júnior); grant 310197/2021-0 (awarded to RS Ferreira), grant 309994/2023-3 (awarded to SMF Murta), grant 302041/2022-2 (awarded to RB de Oliveira), grants 436791/2018-8 and 310232/2017-1 (awarded to GHG Trossini). The authors are also funded by: the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) grants APQ-02816-21 (awarded to SMF Murta), APQ-01116-21 (awarded to CO Rezende Junior) and APQ-00789-22 (awarded to RS Ferreira) as well as the Programa INOVA FIOCRUZ grant VPPCB-007-FIO-18-2-94 (awarded to SMF Murta), the Convênio Fiocruz-Institut Pasteur-USP (provided to SMF Murta), the Chamada de Redes Colaborativas de Pesquisa do Instituto René Rachou– Fiocruz Minas (awarded to SMF Murta), and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant 2017/25543-8 (awarded to GHG Trossini).