Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

Antoaneta Y. Sokolova, Susan Wyllie, Stephen Patterson, Sandra L. Oza, Kevin D. Read, Alan H. Fairlamb (Lead / Corresponding author)

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    Abstract

    The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (similar to 27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

    Original languageEnglish
    Pages (from-to)2893-2900
    Number of pages8
    JournalAntimicrobial Agents and Chemotherapy
    Volume54
    Issue number7
    DOIs
    Publication statusPublished - Jul 2010

    Keywords

    • BLOOD-STREAM FORMS
    • TRICHOMONAS-VAGINALIS
    • COMBINATION THERAPY
    • ESCHERICHIA-COLI
    • BRUCEI
    • NIFURTIMOX
    • PA-824
    • CHEMOTHERAPY
    • TUBERCULOSIS
    • METABOLISM

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