The anticancer drug tirapazamine has antimicrobial activity against Escherichia coli, Staphylococcus aureus and Clostridium difficile

Authors

  • Zarna Shah,

    1. Department of Biochemistry, McGill University, Montréal, QC, Canada
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  • Raya Mahbuba,

    1. Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
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  • Bernard Turcotte

    Corresponding author
    1. Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
    2. Department of Medicine, McGill University Health Centre, McGill University, Montréal, QC, Canada
    • Department of Biochemistry, McGill University, Montréal, QC, Canada
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Correspondence: Bernard Turcotte, Department of Medicine, Room H5.74, McGill University Health Centre, 687 Pine Ave. West, Montréal, QC, Canada H3A 1A1. Tel.: 514 934 1934 ext. 35842; fax: 514 843 2819; e-mail: bernard.turcotte@mcgill.ca

Abstract

Rapidly increasing bacterial resistance to existing therapies creates an urgent need for the development of new antibacterials. Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4 dioxide) is a prodrug undergoing clinical trials for various types of cancers. In this study, we showed that TPZ has antibacterial activity, particularly at low oxygen levels. With Escherichia coli, TPZ was bactericidal under both aerobic and anaerobic conditions. Escherichia coli mutants deficient in homologous recombination were hypersusceptible to TPZ, suggesting that drug toxicity may be due to DNA damage. Moreover, E. coli strains deleted for genes encoding putative reductases were resistant to TPZ, implying that these enzymes are responsible for conversion of the prodrug to a toxic compound. Fluoroquinolone-resistant E. coli strains were as susceptible to TPZ as a wild-type strain. Methicillin-resistant Staphylococcus aureus strains were also susceptible to TPZ (MIC = 0.5 μg mL−1), as were pathogenic strains of Clostridium difficile (MIC = 7.5 ng mL−1). TPZ may merit additional study as a broad-spectrum antibacterial, particularly for anaerobes.

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