title: The anticancer drug tirapazamine has antimicrobial activity against Escherichia coli, Staphylococcus aureus and Clostridium difficile.
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.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC, Canada.
authors.forename: Zarna
authors.initials: Z
authors.lastname: Shah
authors.forename: Raya
authors.initials: R
authors.lastname: Mahbuba
authors.forename: Bernard
authors.initials: B
authors.lastname: Turcotte
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D059767:Recombinational DNA Repair / Q000235:genetics; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D024841:Fluoroquinolones; D014227:Triazines; D000077704:Tirapazamine; D003577:Cytochrome P-450 Enzyme System
keywords: anaerobia; antibiotics; prodrug; reductase