Polymyxin antibiotics induce nephrotoxicity through the selective inhibition of Complex I-dependent respiration in mouse and rat mitochondria

The polymyxin antibiotics colistin (polymyxin E) and polymyxin B remain important for the treatment of severe Gram-negative infections, although their clinical use is limited by frequent cases of nephrotoxicity (Gai et al. 2019 ). In clinical cohorts, polymyxin-associated acute kidney injury (AKI) is common and occurs in approximately 30–50% of treated patients (Zavascki and Nation 2017 ; Oliota et al. 2019 ; Wang et al. 2022 ). Polymyxin-associated neurotoxicity is reported substantially less frequently (3%) than nephrotoxicity (Wagenlehner et al. 2021 ). Owing to the high incidence rate of AKI, the clinical application of polymyxins was reduced in the early 1970s; however, polymyxins are still widely used in clinical practice worldwide because of the increasing burden of infections caused by multidrug-resistant pathogens (Vaara 2019 ). Polymyxin-induced nephrotoxicity is characterised by acute tubular injury driven by the accumulation of colistin and polymyxin B in renal proximal tubular epithelial cells (Manchandani et al. 2017 ; Gai et al. 2019 ). Clinically, colistin and polymyxin B share a similar antibacterial mechanism and spectrum against susceptible Gram-negative bacteria (Poirel et al. 2017 ); however, colistin appears to cause greater nephrotoxicity than polymyxin B (Özdede et al. 2026 ). High polymyxin exposure, baseline renal impairment, older age (particularly > 65 years), the presence of sepsis or septic shock, diabetes, hypoalbuminemia and concomitant vancomycin or vasopressor administration have been associated with increased AKI risk (Wang et al. 2022 ). In addition, bacterial infection-related endotoxemia induces mitochondrial dysfunction and related kidney damage, which amplifies antibiotic toxicity (Makrecka-Kuka et al. 2019 ). The most clinically actionable factors to limit the toxicity of these agents are dose optimisation and the avoidance of additional nephrotoxins, especially vancomycin, aminoglycosides, loop diuretics, calcineurin inhibitors, and nonsteroidal anti-inflammatory drugs (Nation et al. 2019 ). Despite extensive preclinical evidence supporting antioxidant and cytoprotective strategies, clinical evidence for the pharmacological prevention of polymyxin-induced nephrotoxicity remains limited (Nation et al. 2019 ).