With the rising incidences of antimicrobial resistance (AMR) and the diminishing options of novel antimicrobial agents, it is paramount to decipher the molecular mechanisms of action and the emergence of resistance to the existing drugs. Polymyxin, a cationic antimicrobial lipopeptide, is used to treat infections by Gram-negative bacterial pathogens as a last option. Though polymyxins were identified almost seventy years back, their use has been restricted owing to toxicity issues in humans. However, their clinical use has been increasing in recent times resulting in the rise of polymyxin resistance. Moreover, the detection of “mobile colistin resistance ()” genes in the environment and their spread across the globe have complicated the scenario. The mechanism of polymyxin action and the development of resistance is not thoroughly understood. Specifically, the polymyxin-bacterial lipopolysaccharide (LPS) interaction is a challenging area of investigation. The use of advanced biophysical techniques and improvement in molecular dynamics simulation approaches have furthered our understanding of this interaction, which will help develop polymyxin analogs with better bactericidal effects and lesser toxicity in the future. In this review, we have delved deeper into the mechanisms of polymyxin-LPS interactions, highlighting several models proposed, and the mechanisms of polymyxin resistance development in some of the most critical Gram-negative pathogens.

中文翻译：

---

多粘菌素-LPS 相互作用的作用模式和耐药性发展的分子概述

随着抗菌药物耐药性 (AMR) 发生率的上升和新型抗菌药物的选择不断减少，破译分子作用机制和现有药物耐药性的出现至关重要。多粘菌素是一种阳离子抗菌脂肽，用于治疗革兰氏阴性细菌病原体感染，作为最后的选择。尽管多粘菌素在近七十年前就已被发现，但由于对人类的毒性问题，其使用受到限制。然而，近年来它们的临床使用不断增加，导致多粘菌素耐药性上升。此外，环境中“移动粘菌素抗性（）”基因的检测及其在全球范围内的传播使情况变得更加复杂。多粘菌素的作用机制和耐药性的发展尚不完全清楚。具体来说，多粘菌素-细菌脂多糖（LPS）相互作用是一个具有挑战性的研究领域。先进生物物理技术的使用和分子动力学模拟方法的改进进一步加深了我们对这种相互作用的理解，这将有助于将来开发出杀菌效果更好、毒性更小的多粘菌素类似物。在这篇综述中，我们深入研究了多粘菌素-LPS相互作用的机制，重点介绍了提出的几种模型，以及一些最关键的革兰氏阴性病原体中多粘菌素耐药性发展的机制。