Infections caused by multi-drug resistant (MDR) bacterial pathogens are a leading cause of mortality and morbidity across the world. Indiscriminate use of broad-spectrum antibiotics has seriously affected this situation. With the diminishing discovery of novel antibiotics, new treatment methods are urgently required to combat MDR pathogens. Polymyxins, the cationic lipopeptide antibiotics, discovered more than half a century ago, are considered to be the last-line of antibiotics available at the moment. This antibiotic shows a great bactericidal effect against Gram-negative bacteria. Polymyxins primarily target the bacterial membrane and disrupt them, causing lethality. Because of their membrane interacting mode of action, polymyxins cause nephrotoxicity and neurotoxicity in humans, limiting their usability. However, recent modifications in their chemical structure have been able to reduce the toxic effects. The development of better dosing regimens has also helped in getting better clinical outcomes in the infections caused by MDR pathogens. Since the mid-1990s the use of polymyxins has increased manifold in clinical settings, resulting in the emergence of polymyxin-resistant strains. The risk posed by the polymyxin-resistant nosocomial pathogens such as the Enterobacteriaceae group, Pseudomonas aeruginosa, and Acinetobacter baumannii, etc. is very serious considering these pathogens are resistant to almost all available antibacterial drugs. In this review article, the mode of action of the polymyxins and the genetic regulatory mechanism responsible for the emergence of resistance are discussed. Specifically, this review aims to update our current understanding in the field and suggest possible solutions that can be pursued for future antibiotic development. As polymyxins primarily target the bacterial membranes, resistance to polymyxins arises primarily by the modification of the lipopolysaccharides (LPS) in the outer membrane (OM). The LPS modification pathways are largely regulated by the bacterial two-component signal transduction (TCS) systems. Therefore, targeting or modulating the TCS signalling mechanisms can be pursued as an alternative to treat the infections caused by polymyxin-resistant MDR pathogens. In this review article, this aspect is also highlighted.

由耐多药 (MDR) 细菌病原体引起的感染是全世界死亡率和发病率的主要原因。滥用广谱抗生素已经严重影响了这种情况。随着新型抗生素的发现越来越少，迫切需要新的治疗方法来对抗 MDR 病原体。半个多世纪前发现的阳离子脂肽类抗生素多粘菌素被认为是目前可用的最后一类抗生素。这种抗生素对革兰氏阴性菌显示出很强的杀菌作用。多粘菌素主要针对细菌膜并破坏它们，从而导致致命性。由于其膜相互作用的作用方式，多粘菌素会导致人体肾毒性和神经毒性，从而限制了它们的可用性。然而，最近对其化学结构的修改已经能够减少毒性作用。更好的给药方案的开发也有助于在 MDR 病原体引起的感染中获得更好的临床结果。自 1990 年代中期以来，多粘菌素在临床环境中的使用越来越多，导致出现了多粘菌素抗性菌株。多粘菌素抗性医院内病原体带来的风险，例如肠杆菌科群，铜绿假单胞菌，鲍曼不动杆菌，考虑到这些病原体对几乎所有可用的抗菌药物都具有抗药性，因此是非常严重的。在这篇综述文章中，讨论了多粘菌素的作用方式和导致耐药性出现的遗传调控机制。具体而言，本综述旨在更新我们目前在该领域的理解，并提出可用于未来抗生素开发的可能解决方案。由于多粘菌素主要针对细菌膜，因此对多粘菌素的抗性主要通过外膜 (OM) 中脂多糖 (LPS) 的修饰产生。LPS 修饰途径主要受细菌双组分信号转导 (TCS) 系统的调控。所以，可以寻求靶向或调节 TCS 信号机制作为治疗由多粘菌素抗性 MDR 病原体引起的感染的替代方法。在这篇评论文章中，这方面也被强调了。