ArticleArchives of toxicology2026
Polymyxin antibiotics induce nephrotoxicity through the selective inhibition of Complex I-dependent respiration in mouse and rat mitochondria.
Article in Archives of toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Colistin and polymyxin B are last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria; however, their clinical use is limited by considerable nephrotoxicity. Mitochondrial dysfunction has been proposed as one mechanism that contributes to polymyxin-induced kidney injury, but the precise mitochondrial target remains unclear. In the present study, we investigated the effects of colistin and polymyxin B on mitochondrial respiratory complexes. NMRI mice were treated subcutaneously with colistin or polymyxin B (20 mg/kg) every 8 h for a total of six times, which resulted in the accumulation of colistin and polymyxin B 29 and 40 μg/g kidney tissue, respectively. Both polymyxins increased the expression of markers of tubular damage up to 29-fold and induced mitochondrial dysfunction in the kidney. In in vitro experiments using mitochondria from intact kidneys, low concentrations of colistin inhibited Complex I-dependent respiration in the OXPHOS state, with an IC₅₀ of approximately 5 μg/mL. This effect was Complex I-specific because at 5 μg/mL, colistin and polymyxin B did not impair respiration supported by other respiratory chain complexes or compromise mitochondrial membrane integrity. Similar Complex I inhibition by polymyxins was detected in vitro in rat kidney mitochondria. In conclusion, our findings identify mitochondrial Complex I as a sensitive target of colistin and polymyxin B and suggest that inhibition of Complex I-dependent respiration is a key driver of polymyxin-induced nephrotoxicity. This mechanism provides a toxicological framework for understanding interactions between polycationic peptide antibiotics and mitochondrial respiration and may support the selection and optimisation of safer antimicrobial peptides.
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