B-rich colistin and B-pure colistin as novel strategies to increase the therapeutic window of polymyxin antibiotic therapy.

The rise of multidrug-resistant bacteria has made necessary the reintroduction of legacy antibiotics, such as colistin, only used as last-resort due to its concerning derived nephro- and neuro-toxicities. This lipopeptide antibiotic is primarily composed of two main components, colistin A and colistin B. However, their individual toxicological profiles remain poorly understood. This study explores the potential of purified colistin B as a safer alternative to the current colistin-based antibiotic therapy. Using the zebrafish embryo model, we assessed and compared the lethality and neurotoxic effects of two colistin mixtures formulations with different proportions of colistin A and B, and the toxicities of both purified primary components. Additionally, we investigated their respective mechanisms of toxicity and the possibility of preventing their toxic effects using three antioxidant compounds. In zebrafish embryos, colistin B has a significantly lower toxicity profile than colistin A, and in accordance, a colistin mixture mainly composed of colistin B induces significantly less toxicity than a mixture with colistin A as the main component. Moreover, the A-rich colistin mixture significantly increased AChE activity whereas the B-rich colistin mixture did not. Furthermore, we demonstrate for the first time that colistin A and colistin B have distinct mechanisms of toxicity. Notably, only colistin B toxicity is preventable by pre-exposure to antioxidant compounds, whereas co-exposure provides no protective effect. Our findings open a new door towards B-rich or B-pure colistin-based formulations as safer alternatives to current polymyxin therapies, potentially improving their therapeutic window by reducing their adverse effects.