Consistent with these results, in vitro assays showed high binding affinity of polymyxin B to DNA. Notable increases in γH2AX foci (indicative of double-stranded breaks) were observed in both cell culture (up to ~ 44% cells with 5+ foci at 24 h, p < 0.05) and mice treated with polymyxin B (up to ~ 25%, p < 0.05). Kidneys were collected over 48 h and investigated for histopathology and DNA damage. Time-course studies were performed using a mouse nephrotoxicity model (cumulative 72 mg/kg). Human proximal tubular cells were treated with polymyxin B (12.5–100 μM) for up to 24 h and showed a significant increase in micronuclei frequency, as well as abnormal mitotic events (over 40% in treated cells, p < 0.05). Here, we examined the pathways which led to polymyxin B induced cell death in vitro and in vivo. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Polymyxins are ‘last-resort’ antibiotics against Gram-negative ‘superbugs’ however, nephrotoxicity remains a key impediment in their clinical use. Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health.
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