Breaking the Toxicity-Efficacy Dilemma of Polymyxins: Advances in Synergists.

Polymyxins are considered last-resort antibiotics for multidrug-resistant Gram-negative bacteria. However, their clinical utility is limited by toxicities, particularly nephrotoxicity and neurotoxicity, as well as the emergence of resistance. This review addresses these challenges and evaluates strategic interventions aimed at enhancing the efficacy of polymyxins while mitigating their adverse effects. Combination therapies have emerged as a cornerstone strategy. These therapies can be categorized into five frameworks: structural barrier disruption, bioenergetic flux modulation, metabolic homeostasis disruption, resistance neutralization, and virulence disarming. In addition to synergistic agents, complementary strategies such as detoxifying adjuvants and advanced delivery systems have been systematically integrated to overcome the intrinsic limitations of polymyxins. Collectively, these multifaceted strategies enhance the antibacterial activity of polymyxins against Gram-negative bacteria, while simultaneously reducing effective doses, minimizing toxicity, and mitigating the development of resistance. These innovations represent a pivotal advance in revitalizing polymyxin therapy in the era of multidrug resistance.