Combination therapy using nitro compounds improves the efficacy of experimental Chagas disease treatment

Mazzeti, Ana Lia; Gonçalves, Karolina Ribeiro; Mota, Suianne Leticia Antunes; Pereira, Dário Elias; Diniz, Lívia de Figueiredo; Bahia, Maria Terezinha

doi:10.1017/s0031182021001001

Cited by 8 publications

(1 citation statement)

References 56 publications

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“…However, both current cornerstone therapies against second stage g-HAT, NECT and fexinidazole, now rely on nitroaromatic compounds leaving them vulnerable to drug resistance and cross-resistance (Sokolova et al, 2010b). Due to the efficacy of fexinidazole against apparently all kinetoplastida parasites, the drug is being actively considered as a possible treatment for American trypanosomiasis and multiple forms of Leishmania infections (Bahia et al, 2014; Patterson and Fairlamb, 2019; Mazzeti et al, 2021). While fexinidazole’s clinical approval may represent a considerable therapeutic advancement, there are major gaps in our understanding of how it kills trypanosomes and sources of drug resistance and nitroaromatic cross-resistance (Sokolova et al, 2010b; Hall et al, 2011; Wyllie et al, 2016b).…”

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confidence: 99%

Fexinidazole induced cytotoxicity is distinct from related anti-trypanosome nitroaromatic drugs

Rogers,

Berg,

Ramirez

et al. 2023

Preprint

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Nitroaromatic drugs are of critical importance for the treatment of trypanosome infections in Africa and the Americas. Fexinidazole recently joined benznidazole and nifurtimox in this family when it was approved as the first oral therapy against Human African trypanosomiasis (HAT). Nitroaromatic prodrugs are bioactivated by the trypanosome-specific type I nitroreductase (NTR) enzyme that renders the compounds trypanocidal. A caveat to the specificity of NTR activation is the potential for drug resistance and cross-resistance that can arise if NTR expression or functionality is altered through mutation. The outcomes of NTR bioactivation of nitroaromatic compounds is variable but can include the formation highly reactive open chain nitriles that can damage biomolecules including DNA. A proposed mechanism of action of nitroaromatic compounds is the formation of reactive oxygen species (ROS) resulting in the formation of trypanocidal levels of DNA damage. Fexinidazole made its way to clinical approval without a significant interrogation of its effects on trypanosome biology and a limited understanding of its mechanism of action. Early reports mentioned fexinidazole potentially affects DNA synthesis but without supporting data. In this study, we evaluated and compared the cytotoxic effects of nifurtimox, benznidazole, and fexinidazole onTrypanosoma bruceiusing in vitro analyses. Specifically, we sought to differentiate between the proposed effects of nitroaromatics on DNA damage and DNA synthesis. Toward this goal we generated a novel γH2A-based flow cytometry assay that reports DNA damage formation in conjunction with cell cycle progression. Here we report that fexinidazole’s cytotoxic outcomes are distinct from the related drugs nifurtimox and benznidazole. Specifically, we show that fexinidazole treatment results in a pronounced defect in DNA synthesis that reduces the population of parasites in S phase. In contrast, treatment with nifurtimox and benznidazole appear accumulate DNA damage early in cell cycle and result in a defective G2population. The findings presented here bring us closer to understanding the anti-trypanosomatid mechanisms of action of nitroaromatic compounds, which will promote improved drug design and help combat potential drug resistance in the future. Our findings also highlight DNA synthesis inhibition as a powerful anti-parasitic drug target.

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