Abstract：
The treatment of sepsis caused by multidrug-resistant (MDR) Gram-negative bacterial infections remains challenging. With these pathogens exhibiting resistance to carbapenems and new generation cephalosporins, the traditional antibiotic polymyxin B (PMB) has reemerged as a critical treatment option. However, its severe neurotoxicity and nephrotoxicity greatly limit the clinical application. Therefore, we designed negatively charged high-density lipoprotein (HDL) mimicking nanodiscs as a PMB delivery system, which can simultaneously reduce toxicity and enhance drug efficacy. The negative charge prevented the PMB release in physiological conditions and binding to cell membranes, significantly reducing toxicity in mammalian cells and mice. Notably, nanodisc-PMB exhibits superior efficacy than free PMB in sepsis induced by carbapenem-resistant Acinetobacter baumannii (CRAB) strains. Nanodisc-PMB shows promise as a treatment for carbapenem-resistant Gram-negative bacterial sepsis, especially caused by Acinetobacter baumannii, and the nanodiscs could be repurposed for other toxic antibiotics as an innovative delivery system. STATEMENT OF SIGNIFICANCE: Multidrug-resistant Gram-negative bacteria, notably carbapenem-resistant Acinetobacter baumannii (CRAB), currently pose a substantial challenge due to the scarcity of effective treatments, rendering Polymyxins a last-resort antibiotic option. However, their therapeutic application is significantly limited by severe neurotoxic and nephrotoxic side effects. Prevailing polymyxin delivery systems focus on either reducing toxicity or enhancing bioavailability yet fail to simultaneously achieve both. In this scenario, we have developed a distinctive HDL-mimicking nanodisc for polymyxin B, which not only significantly reduces toxicity but also improves efficacy against Gram-negative bacteria, especially in sepsis caused by CRAB. This research offers an innovative drug delivery system for polymyxin B. Such advancement could notably improve the therapeutic landscape and make a significant contribution to the arsenal against these notorious pathogens.
摘要：
由多重耐药（MDR）革兰氏阴性细菌感染引起的败血症的治疗仍然具有挑战性。随着这些病原体对碳青霉烯类和新一代头孢菌素类药物表现出耐药性，传统抗生素多粘菌素B(PMB)已重新成为关键治疗选择.然而,严重的神经毒性和肾毒性极大地限制了临床应用。因此,我们设计了带负电荷的高密度脂蛋白（HDL），模拟纳米盘作为PMB递送系统，可以同时降低毒性和增强药物疗效。负电荷阻止PMB在生理条件下释放并与细胞膜结合，显著降低哺乳动物细胞和小鼠的毒性。值得注意的是,nanodisc-PMB在耐碳青霉烯鲍曼不动杆菌（CRAB）菌株诱导的脓毒症中表现出比游离PMB更好的疗效。Nanodisc-PMB有望治疗耐碳青霉烯的革兰氏阴性菌败血症，特别是由鲍曼不动杆菌引起的，纳米圆盘可以作为创新的输送系统用于其他有毒抗生素。重要性声明：多重耐药革兰氏阴性菌，特别是碳青霉烯类耐药鲍曼不动杆菌（CRAB），由于缺乏有效的治疗方法，目前构成了巨大的挑战，使多粘菌素成为最后的抗生素选择。然而,它们的治疗应用受到严重的神经毒性和肾毒性副作用的显著限制。现有的多粘菌素递送系统专注于降低毒性或提高生物利用度,但不能同时实现两者。在这种情况下，我们为多粘菌素B开发了一种独特的HDL模拟纳米盘，这不仅显着降低毒性，而且还提高了对革兰氏阴性菌的功效，尤其是由CRAB引起的脓毒症。这项研究为多粘菌素B提供了一种创新的药物递送系统。这种进步可以显着改善治疗环境，并为针对这些臭名昭著的病原体的武器库做出重大贡献。
