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

Abstract

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