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

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 preexposure

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.